WELCOME TO THE NIH 16th SICKLE
CELL IN FOCUS CONFERENCE.
IT'S SO NICE TO SEE SOME OF YOU
IN PERSON AND I'M MINDFUL THERE
WILL BE OTHERS JOINING USSON
LINE.
WE'RE RUNNING A LITTLE BIT LATE.
I APOLOGIZE.
ALSO THERE MAY BE SOME GLITCHES
BECAUSE IT'S THE FIRST TIME
WE'RE BACK AFTER COVID SO DO
EXCUSE US AND TELL US HOW WE CAN
DO BETTER.
WE WILL BEGIN SHORTLY WITH
REMARKS FROM DR. JULIE PANEPINTO
THE DIRECTOR OF BLOOD DISEASES
AT NHLBI AND FOLLOWED BY RICK
CHARLES ACTING SCIENTIFIC
DIRECTOR.
ALL OF YOU SHOULD HAVE GOT A
COPY OF THE OFFICIAL PROGRAM
MAILED TO ATTENDEES AND FOUND IN
THE CONFERENCE WEBSITE.
IF YOU'RE JOINING US FROM THE
ONLINE VIDEOCAST YOU CAN SUBMIT
S LIKE USING THE CHAT BOX
FOLLOWING EACH TALK.
IF WE ARE UNABLE TO GET YOUR
QUESTIONS, WE'LL E-MAIL THEM TO
THE SPEAKER FOR RESPONSE LATER.
ANOTHER THING SOME OF OUR
SPEAKERS HAVE SENT IN
PRE-RECORDED TALKS BUT MIGHT BE
AVAILABLE FOR A FEW MINUTES TO
ANSWER QUESTIONS LIVE VIRTUALLY.
IS SO I'M REALLY EXCITED THAT
WE'RE ABLE TO BRING THIS
TOGETHER NOW ON SITE AND LOOK
FORWARD TO A SUCCESSFUL
CONFERENCE AND THANK YOU ALL FOR
JOINING US.
SO WITH THAT I'LL HAND IT OVER
TO JULIE.
>> GOOD MORNING.
I ECHO THE SENTIMENT IT'S GOOD
TO SEE SOME OF YOU IN PERSON
AFTER PARTICIPATING IN THIS
VIRTUALLY FOR A FEW YEARS.
SO I'M HERE TO PROVIDE JUST A
VERY BRIEF OVERVIEW OF SOME OF
THE RESEARCH WE FUND THROUGH THE
BLOOD DIVISION AT THE NHLBI IN
SICKLE CELL DISEASE WE FUND
EARLY BASIC TRANSITIONAL
RESEARCH THROUGH THE SHRINE
COLLABORATIVE WITH NIDDK THAT
STIMULATES RESEARCH IN
NON-MALIGNANT HEMATOLOGY AND WE
ALSO FUND CLINICAL TRIALS AT ALL
PHASES FROM REALLY PHASE 1 OF
IMPLEMENTATION RESEARCH AND
CHRONIC BLOOD TRANSFUSIONS AND
THE IMPACT IT MAY HAVE ON ADULTS
AND MORTALITY IN SICKLE CELL
DISEASE.
WE'RE LOOKING AT THE AFFECT OF
ARGENINE AND LOOKING AT SYSTEMS
OF CARE.
CONNECTING ADULTS WITH SICKLE
CELL DISEASE TO SICKLE CELL
DISEASE SPECIALISTS AND
IMPROVING TIMELINESS OF CARE FOR
INDIVIDUALS PRESENTING WITH PAIN
TO THE EMERGENCY DEPARTMENT.
WE HAVE GLOBAL INITIATIVES.
TO HIGHLIGHT TWO WE HAVE BLOOD
SAFE OUT OF AFRICA THAT AIMS TO
INCREASE BLOOD SAFETY IN
ADDITION TO INCREASING BLOOD
DONORS WHICH IS A BIG NEED AND
ENHANCING DELIVERY OF BLOOD AND
THAT WOULD BE A HUGE IMPACT ON
OUR SICKLE CELL DISEASE
INDIVIDUALS LIVING WITH SICKLE
CELL DISEASE.
WE ALSO FUND SICKLE IN AFRICA
WHICH IN ITS RENEWAL PHASE IN
THE FIRST FACE WE BUILT
INFRASTRUCTURE IN A LARGE
REGISTRY WHICH MY UNDERSTANDING
IS PROBABLY OVER 15,000
INDIVIDUALS LIVING WITH DEVELOPS
IN THE AFRICAN COUNTRIES.
THE RENEWAL PHASE BUILT ON THE
INFRASTRUCTURE AND TO IMPLEMENT
LOCAL STANDARDS OF CARE AND DO
OTHER DISSEMINATION AND
IMPLEMENTATION WORK.
WE ALSO THEN FUND OUR CURES
INITIATIVE.
MANY OF YOU KNOW THIS
INITIATIVE.
WE'RE FUNDING CURRENTLY TWO GENE
THERAPY TRIALS.
ONE IS CALLED THE GRASS TRIAL
WHICH IS A PHASE 2 CLINICAL GENE
THERAPY TRAIL USING A VECTOR TO
INCREASE FETAL HEMOGLOBIN
EXPRESSION RECRUITING AND DOING
WELL WITH RECRUITMENT.
WE HOPE TO HAVE OPEN IN THE NEXT
ACADEMIC OR CALENDAR YEAR 2024
THE CRISPR TRIAL USING CRISPR
KAS 9 NUCLEUS AND THAT'S A PHASE
1 STUDY WE DO HOPE WILL BE OPEN
THIS COMING SUMMER.
THOSE ARE A FEW HIGHLIGHTS.
WE FUND MANY THINGS AND A CAN'T
MENTION ALL OF THAT.
I ENCOURAGE ALL OF TO YOU PLEASE
SEND US YOUR RESEARCH AND
PROPOSAL.
WE WOULD LIKE TO FUND SICKLE
CELL DISEASE RESEARCH.
PLEASE CONTACT MYSELF OR OUR
STAFF TO GUIDE YOU THROUGH THE
PROCESS.
THAT'S WHAT WE'RE HERE FOR
ESPECIALLY IF YOU'RE THINKING
ABOUT ANY TYPE OF CLINICAL
TRIAL.
THANK YOU AND I'LL TURN THIS
OVER TO MAYBE THE START OF THE
NEXT SESSION IF I DON'T SEE
DR. CHILDS HERE.
I'D LIKE TO INTRODUCE DR. RICK
CHARLES OUR CLINICAL DIRECTOR
AND ACTING SCIENTIFIC DIRECTOR.
RICK HAS ALWAYS SUPPORTED THE
SICKLE CELL PROGRAM AND IT'S
VERY NICE OF YOU TO MAKE TIME.
THANK YOU.
>> GOOD MORNING, EVERYONE.
BESIDES INVESTIGATOR AND
CLINICAL DIRECTOR I'M ACTING
SCIENTIFIC DIRECTOR SO I
APOLOGIZE FOR BEING LATE THIS
MORNING.
I WANT TO WELCOME EVERYONE HERE
TO THE 16th ANNUAL SICKLE CELL
IN FOCUS CONFERENCE.
FINALLY AFTER MORE THAN THREE
YEARS OF THE PUBLIC HEALTH
EMERGENCY AND WEARING MASKS WE
CAN ALL MEET WITH MASKS OFF OF
OUR FACE AND AS MANY OF YOU
HEARD THERE WAS SOME FEAR ABOUT
A GOVERNMENT SHUT DOWN A COUPLE
WEEKS AGO AND I WAS IN
PARTICULAR THINKING ABOUT ALL
THE THINGS THAT HAPPENED IN
GOVERNMENT SHUTDOWN AND THINKING
ABOUT THE MEETING AND HOW
TERRIBLE IT WOULD BE IF WE HAD
TO CANCEL THIS MEETING.
THANKFULLY THE STARS ALIGNED,
GOVERNMENT DIDN'T SHUT DOWN AND
WE'RE ALL HERE TODAY.
I WANT TO GIVE A QUICK
BACKGROUND ON THE NIH FOR THOSE
THAT ARE NOT FAMILIAR WITH THE
NIH.
WE WERE ESTABLISHED AS AN ENTITY
IN 1887 WITH THE INTENTION FOR
THE NIH FOR THE WORLD'S PREMIER
BIOMEDICAL RESEARCH
ORGANIZATION.
WE'RE DIVIDED INTO INTRAMURAL
AND EXTRAMURAL PROGRAMS.
AT THE INTRAMURAL PROGRAM
CLINICAL RESEARCH IS CONDUCTED
IN THE NIH CLINICAL CENTER WHICH
IS OUR RESEARCH HOSPITAL TO
COMPLETELY DEVOTED TO CLINICAL
RESEARCH.
WE HAVE MORE THAN 1600 CLINICAL
RESEARCH TRIALS AND ALL CARE
DELIVERED AT THE CLINICAL CENTER
IS FREE OF CHARGE.
ONE OF THE MAJOR CLINICAL
RESEARCH EMPHASIS IS TO STUDY
THE PATHOPHYSIOLOGY OF DISEASES
INCLUDING DISEASES LIKE SICKLE
CELL ANEMIA AND DEVELOP NEW AND
FIRST IN HUMAN THERAPEUTICS FOR
THOSE DISEASES.
WE AIM TO DO RESEARCH HERE THAT
CANNOT EASILY BE DONE OUTSIDE OF
THE NIH CAMPUS.
IN PARTICULAR RESEARCH WHERE
MAYBE THERE'S NOT ENOUGH
IMMEDIATE EVIDENCE TO SUPPORT
CLINICAL TRIALS FOR GRANT
FUNDING BUT WHERE THERE'S ENOUGH
BIOLOGICAL EVIDENCE TO TAKE
SOMETIMES A LEAP OF FAITH TO DO
SOME OF THESE FIRST IN HUMAN
TRIALS IF SUCCESSFUL CAN BE
POTENTIALLY PARADIGM SHIFTING
AND LEAD TO THE EVIDENCE THAT
WOULD SUPPORT GRANT-FUNDED
TRIALS IN THE EXTRAMURAL
COMMUNITY.
THERE'S BEEN NUMEROUS ADVANCES
IN MEDICINE THAT OCCURRED
BECAUSE OF RESEARCH CONDUCTED AT
THE NIH CLINICAL CENTER.
SOME INCLUDE THINGS LIKE THE
FIRST DEMONSTRATION OF
CHEMOTHERAPY COULD BE EFFECTIVE
FOR CANCER.
THE FIRST CURE OF CANCER OF
HODGKIN'S DISEASE AND USE OF
BLOOD LIPID LEVELS AS A MARKER
OF CARDIOVASCULAR DISEASE AND
THE FIRST THERAPEUTIC FOR AZT.
THE FIRST DEMONSTRATION
IMMUNOSUPPRESSION CAN BE USED TO
TREAT AUTOIMMUNE DISEASES AND
THE FIRST DEMONSTRATION THAT
IMMUNOTHERAPY COULD BE
SUCCESSFUL TO TREAT PATIENTS
WITH CANCER.
NHLBI IS PROUD TO SUPPORT
CUTTING-EDGE RESEARCH FOR SICKLE
CELL DISEASE AND IN THE PROGRAM
THAT SUPPORT INCLUDES BOTH
NATURAL HISTORY STUDIES WHERE WE
DO OMICS TYPE OF RESEARCH AND
DEEP PHENOTYPING ON PATIENTS AS
WELL INVESTIGATOR INITIATED
BENCH TO BEDSIDE RESEARCH AIMED
AT DEVELOPING NEW THERAPEUTICS
FOR SICKLE CELL DISEASE.
AT THE DIR WE HAVE TWO SEPARATE
BRANCHES MADE OF 100 STAFF THAT
FOCUS RESEARCH ON SICKLE CELL
THE SICKLE CELL BRANCH LED BY
DR. SWEE LAY THEIN AND
DR. TISDALE.
THEY'VE DONE PIONEERING RESEARCH
THAT'S LED TO NEW THERAPEUTICS
AND SOME OF THAT RESEARCH
INCLUDES THINGS LIKE THE
DEVELOPMENT OF AND INITIAL
TESTING IN SICKLE CELL DISEASE
PATIENTS AND PREVENT OCCLUSION
AND A FINDING THAT LED TO AGAIN
ET -- GENETIC REACTIVATION OF
HEMOGLOBIN AND FINDING HIGH CURE
RATES AND NO GRAPH VERSUS HOST
DISEASE IN THE MAJORITY OF
PATIENTS TREATED WITH THESE
REGIMENTS AND RECENTLY DR. FITU
EXTENDED THE APPROACH TO INCLUDE
PATIENTS UNDERGOING HAPLODEMIGO
TRANSPLANTATION USING THAT
APPROACH AS WELL.
MOST RECENTLY GENETICALLY
CORRECT THE BETA GLOBULIN GENE
RESULTING IN COMPLETE EVASION OF
EVENTS.
WE'RE PROUD OF ALL OF THESE
INVESTIGATORS WITHIN THE NHLBI
CONDUCTING THIS PENE EARRING
WORK THAT IS DIRECTLY IMPROVED
THE LIVES OF PATIENTS WITH
SICKLE CELL IN SOME PATIENTS HAS
CURED THESE PATIENTS.
WE IS HAVE DONE MUCH AS THE
FORMER DIRECTOR OF THE NHLBI WAS
FAMOUS FOR SAYING WE'VE DONE
MUCH, WE HAVE MUCH TO DO.
IN THE COMING YEARS THE NHLBI
WILL COMMIT ADDITIONAL MONEY AND
RESOURCES TO CONTINUE RESEARCH
IN SICKLE CELL AND PROUD TO
ANNOUNCE A MAJOR FOCUS OF THAT
RESEARCH WILL BE TO DEVELOPING
NEW IN VIVO GENE THERAPIES FOR
THIS DISEASE AIMS AT GENETICALLY
CORRECTING THE HEMATOPOIETIC
STEM CELLS AND THEY PLAN TO
DEVELOP A GENE THAT THERAPY
CORPS FACILITY AIMED AT CELLULAR
ENGINEERING FOR A MAJOR AMOUNT
OF THAT WORK WILL BE FOCUSSED ON
SICKLE CELL ANEMIA.
I'M ALSO HAPPY TO ANNOUNCE OUR
PARTNERSHIP WITH AN ORGANIZATION
IN JAMAICA IS MOVING ALONG TOO.
OUR HOPE IS TO ESTABLISH A
FORMAL PARTNERSHIP WITH OUR
COLLEAGUES IN JAMAICA SO THE
CUTTING-EDGE RESEARCH AND NEW
THERAPEUTICS WE'RE TESTING HERE
AT THE NIH WILL POTENTIALLY BE
AVAILABLE TO OUR JAMAICAN
COLLEAGUES THROUGH TWO CENTER
TRIALS.
ONCE AGAIN, THANK YOU ALL FOR
ATTENDING THIS MEETING.
I HOPE YOU HAVE A GREAT MEETING
AND I WANT TO THANK ALL OF YOU
FOR THE WORK THAT YOU DO EVERY
DAY TO IMPROVE THE QUALITY OF
LIFE AND LONGEVITY OF THOSE
PATIENT WHO'S ARE DEBILITATED
AND HAVE THEIR LIVES SHORTENED
BY THIS TERRIBLE DISEASE.
THANK YOU.
>> NOW WE'LL START WITH THIS
DAY'S PROGRAM.
DR. JENNIFER KNIGHT-MADDEN TAKE
OVER.
>> GOOD AMONG, EVERYBODY.
WELCOME.
THANK YOU FOR GETTING HERE SO ON
TIME AND EARLY BOTH HERE AND
ONLINE.
WE'RE INTO SESSION 1 WHERE WE'RE
LOOKING AT A GLOBAL LOOK AT
SICKLE CELL DISEASE.
WE START WITH TWO IMMINENT
SPEAKERS DR. CHARLES ABRAMS AND
ALEXIS THOMAS.
DR. ABRAMS IS FROM THE
PENNSYLVANIA UNIVERSITY AND VICE
CHAIR FOR RESEARCH AND
SCIENTIFIC OFFICER OF THE
DEPARTMENT OF MEDICINE AT PENN.
OVER THE PAST FEW YEARS HE'S
ALSO LED ANNEST BY THE ASH
RESEARCH COLLABORATIVE TO
DEVELOP A NATIONAL CLINICAL
TRIALS NETWORK WHICH FACILITATES
INTERVENTIONAL TRIALS THAT WILL
LEAD TO MORE RAPID FDA APPROVAL
OF DRUGS DESIGN TO IMPROVE THE
QUALITY OF LIFE FOR SICKLE CELL
PATIENTS AND TO INCREASE THE
SURVIVAL OF INDIVIDUALS WITH
THIS DISORDER.
HIS CO-SPEAKER IS ALEXIS THOMAS
A CHIEF OF THE DIVISION OF
HEMATOLOGY AT CHOC.
SHE HOLDS THE ELIAS SCHWARTS
CHAIR FOR HEMATOLOGY AND SERVED
AS THE PRESIDENT OF ASH IN 2018.
SHE'S A MEMBER OF THE ASH
STEERING COMMITTEE AND USES THE
MEDICAL DEGREE FROM TULANE
UNIVERSITY AND HAS PRACTICED 34
YEARS AND SPECIALIZES IN
PEDIATRIC ANEMIA AND RED CELL
HEMATOLOGY.
I WELCOME DR. ABRAMS AND
THOMPSON TO GIVE THEIR TALK.
>> THANKS, EVERYONE.
CAN WE GET THE FIRST SLIDE ON.
>> SO THANKS AGAIN.
ON BEHALF OF ASH, THE ASH
RESEARCH COLLABORATIVE, MY
PARTNER ALEXIS AND I WOULD LIKE
TO THANK THE ORGANIZERS FOR A
CHANCE TO SHARE WHAT WE'RE
DOING.
SO ABOUT HALF A DOZEN YEARS AGO
THE AMERICAN SOCIETY OF
HEMATOLOGY MADE A COMMITMENT TO
IMPROVE THE LIVES OF INDIVIDUALS
WITH SICKLE CELL DISEASE.
THIS INVOLVED A MULTI-PRONG
PROCESS.
THERE WAS A PORTION DEDICATED TO
ACCESS TO CARE, THERE WAS
PARTNERING WITH FEDERAL AGENCIES
TO HELP EFFECTUATE POLICY
CHANGE.
THERE WAS A FOUNDATION OF THE
SICKLE CELL DISEASE COALITION TO
GIVE A VOICE TO THE COMMUNITY
WITH THIS DISEASE AND THEN THERE
WERE WERE TWO INITIATIVES.
A RESEARCH AND GLOBAL INITIATIVE
THAT ALEXIS AND I ARE GOING TO
BE TALKING ABOUT TODAY.
THE RESEARCH INITIATIVE INVOLVED
THE FORMATION OF THE ASH
RESEARCH COLLABORATIVE IN I
THINK 2018.
SO SUCCINCTLY THIS WAS DESIGN TO
FOSTER LARGE-SCALE
MULTI-INSTITUTIONAL COOPERATIVE
STUDIES TO IMPROVE THE LIVES OF
INDIVIDUALS WITH SICKLE CELL.
AND IT HAS TWO MAIN COMPONENTS
TO IT.
IT HAS A CLINICAL TRIAL NETWORK
I'M GOING TO BE SPENDING SOME
TIME DESCRIBING HERE TODAY AND
THEN ALEXIS IS GOING TO BE
TALKING ABOUT A DATA REGISTRY
PROGRAM.
ALEXIS WILL ALSO BE SPENDING
TIME TALKING ABOUT THE GLOBAL
WORK SPECIFICALLY AN INITIATIVE.
THE CLINICAL TRIAL NETWORK WAS
DESIGN TO ACCELERATE RESEARCH IN
SICKLE CELL DISEASE.
IT'S BEEN DESIGNED TO IMPROVE
THE LIVE OF INDIVIDUALS WITH
THIS DISORDER.
SO WHAT MAKES A CLINICAL TRIAL
NETWORK?
IN OUR MINDS YOU NEED FOUR
THINGS.
FIRST AND FOREMOST IS THE
COMMUNITY.
WE SAID FROM THE BEGINNING WE
WERE BUILDING THIS WITH THE
COMMUNITY NOT FOR THE COMMUNITY.
THE COMMUNITY HAS BEEN
INCREDIBLY INFORMATIVE AT EVERY
STEP AND TALK ABOUT HOW THAT
WORKS IN A BIT.
WE NEED INVESTIGATORS.
WE NEED A TEAM OF COLLEAGUES WHO
HAVE A RICH CULTURE OF DOING
COOPERATIVE RESEARCH AND I'LL BE
SPENDING SOME TIME IN THAT AS
WELL.
WE NEED SPONSORS OF TRIALS AND
WHETHER THAT BE EXTRAMURAL
FUNDED WORK OR FROM THE PRIVATE
SECTOR AND I'LL BE DESCRIBING
WHAT WE CAN DO FOR BOTH OF THOSE
SPONSORS IN A BIT.
ALEXIS WILL TALK ABOUT OUR DATA
REGISTRY OR DATA.
OUR CLINICAL TRIAL NETWORK.
THIS IS WHERE WE STAND TODAY.
WE HAVE 20 DIFFERENT CLINICAL
TRIAL UNITS SCATTERED AND ALIGNS
GEOGRAPHICALLY WITH THE
DISTRIBUTION OF PEOPLE WITH
SICKLE CELL DISEASE.
AND YOU'LL NOTICE THAT EACH OF
THESE CLINICAL TRIAL UNITS IS
COMPOSED OF NOT ONLY A CENTRAL
SITE HUB BUT MULTIPLE OTHER
SITES.
IF YOU WERE TO TOTAL ALL THE
DOTS, JOHN, YOU LOOK LIKE A GOOD
COUNTER, IF I WERE TO ASK YOU
JOHN WOULD SAY IT'S OVER 90.
THERE'S OVER 90 SITES WITH SOME
AFFILIATION WITH OUR NETWORK.
OUR RELATIONSHIP IS DEEPEST WITH
THE 20 SITES LISTED AND SPELLED
OUT RIGHT HERE BUT WE'RE WORKING
TO BRING IN ALL THESE OTHER
SITES.
IF YOU WERE TO TOTAL THEM THEY
CARE FOR OVER 40,000 INDIVIDUALS
WITH SICKLE CELL DISEASE.
THE POTENTIAL OF THE NETWORK IS
ENORMOUS IF YOU THINK MORE THAN
ONE OF EVERY THREE DEVELOPS WITH
SICKLE CELL DISEASE IN THE
COUNTRY IS SOMEHOW TOUCHED WITH
SOME AFFILIATION WITH THIS
NETWORK.
SOME ARE TIGHTER THAN OTHERS BUT
THIS IS WHERE WE'RE MARCHING TO.
SO WE THESE SPONSORS OF TRIALS.
ONE OF THE TYPES OF SPONSORS WE
COULD WORK WITH IS THE PRIVATE
SECTOR OF INDUSTRY.
WE'VE BEEN DOING SEVERAL THINGS
FOR OUR INDUSTRY PARTNERS.
SO ONE, WE'VE BEEN LEVERAGING
THE EXPERTISE OF OUR
INVESTIGATORS WHO ADVISE ON
STUDY DESIGN.
WE'VE ALSO BEEN LEVERAGING THE
EXPERTISE OF OUR COMMUNITY
ADVISORY BOARDS I'LL DESCRIBE IN
A MINUTE.
TO GIVE PERSPECTIVE OF WHETHER A
PATIENT OR PATIENT'S FAMILY
MEMBER MIGHT THINK ABOUT A
PARTICULAR TRIAL AND WE CAN ALSO
CONNECT INDUSTRY WITH THE RIGHT
SITES.
THE COMMUNITY PROGRAM.
IT HAS BEEN AN ESSENTIAL PARTNER
IN EVERY STEP ALONG THE WAY OF
THIS AND SO WE EDUCATE THEM BUT
I THINK THEY PROBABLY EDUCATE US
EVEN MORE.
WE HAVE THIS RELATIONSHIP WHERE
WE INFORM EACH OTHER.
EACH OF OUR CLINICAL TRIAL SITES
HAS A COMMUNITY ADVISORY BOARD
AND SEVERAL MEMBERS OF THOSE
BOARDS HAVE BEEN ELECTED TO A
NATIONAL ADVISORY BOARD THAT
WORKS WITH US AND WITH US WE
RENEWED INDUSTRY SPONSORED
TRIALS AND FORMED FOCUS GROUPS
TO HELP INFORM STUDY DESIGN.
THEY'VE ALSO BEEN HELPFUL AS
WE'VE TRIED TO SET OUR OWN
RESEARCH AGENDA FOR INVESTIGATOR
INITIATED RESEARCH.
THEY'VE DONE A SURVEY OF
EDUCATIONAL MATERIAL OF WHAT
IT'S LIKE TO PARTICIPATE IN A
CLINICAL TRIAL AND WHAT WILL
THAT MEAN FOR ME.
WE IDENTIFIED MATERIAL FOR THIS
PATIENT POPULATION AND
IDENTIFIED GAPS AND WE'RE
WORKING ON FILLING IN THOSE GAPS
BY CREATING NEW ADDITIONAL
EDUCATIONAL MATERIALS.
ANOTHER THING THAT WE'RE DOING
TOGETHER IS TRYING TO HARNESS
THE POWER OF THE NETWORK BY
DESIGNING OUR OWN MULTI-CENTER
INVESTIGATOR INITIATED RESEARCH.
SO THIS IS A COLLABORATION AMONG
OUR INVESTIGATORS.
SO WE'RE WORKING TO DEVELOP
PEER-CONCEIVED, PEER REVIEWED
AND PEER-WRITTEN PARTICLES WE'RE
IN THE PROCESS OF SUBMITTING FOR
EXTRAMURAL FUNDING.
ONE STUDY THAT I'D LIKE TO
MENTION IS ONE WE'RE JUST
WRAPPING UP NOW AND THAT'S THE
COVID-19 VACCINATION TRIAL.
THIS STUDY WAS DESIGN TO ANSWER
TWO FUNDAMENTAL QUESTIONS.
FIRST, IS THE IMMUNITY INDUCED
BY THE COVID VACCINE IN
INDIVIDUALS WITH SICKLE CELL
DISEASE SIMILAR TO THE IMMUNITY
GENERATED IN THE GENERAL
POPULATION.
THE OTHER QUESTION THAT WAS VERY
KEY TO THIS COMMUNITY IS DOES
THE UNIQUE NATURE OF AN mRNA
VACCINE INDUCE TOXICITY.
WILL THIS INDUCE A CRISIS IN ME?
I'M NOT GOING TO GO INTO ALL THE
DETAILS OF THE STUDY BUT I'LL
JUST TELL YOU OUR BOTTOM LINES.
ANTIBODY PRODUCTION LOOKS ROBUST
AND SIMILAR IN THIS PARTICULAR
GROUP OF PATIENTS.
IMPORTANTLY, IT DOESN'T SEEM TO
BE INDUCING EXCESS CRISIS.
SO, TO OUR KNOWLEDGE THIS IS THE
LARGEST mRNA VACCINE TRIAL DONE
IN SECOND HALFED.
THE REASON THIS IS SO IMPORTANT
NOT ONLY FOR COVID BUT mRNA
VACCINES ARE PROBABLY HERE TO
STAY AND PROBABLY WILL BE MANY
MORE mRNA VACCINES INCLUDING
SOME mRNA TECHNOLOGY USED FOR
SICKLE CELL DISEASE FOR
CORRECTIVE THERAPY.
IT'S REASSURING THIS DOESN'T
INDUCE A UNIQUE TOXICITY IN THIS
PATIENT POPULATION.
THIS WAS THE FIRST SAFETY AND
ANTIBODY RESPONSE VACCINE TRIAL
IN VERY YOUNG CHILDREN WITH
SICKLE CELL DISEASE.
I TOLD YOU ABOUT OUR COMMUNITY
WORK AND ABOUT THE INVESTIGATORS
AND ABOUT THE SPONSORS AND NOW
MY PARTNER, ALEXIS, WILL TALK TO
YOU ABOUT OUR DATA REGISTRY.
>> THANK YOU.
I'LL COVER THE DATA HUB AND
LEARNING COMMUNITY AND FINALLY
OUR GLOBAL EFFORTS COULD CONDA.
THE ASH RC DATA HUB IS INTENDED
TO BE APPLIED BROADLY IN
HEMATOLOGY AND BEGUN ITS EFFORTS
IN ONE MALIGNANT AND ONE
NON-MALIGNANT DISORDER.
IT'S FUNDAMENTALLY MEANT TO BE A
REAL WORLD DATA SOURCE TO
ACTUALLY DRIVE RESEARCH AS WELL
AS CLINICAL CARE.
AND WE'VE HAD THE ELECTRONIC
MEDICAL SYSTEM AND WE ANTICIPATE
TO IT TO INGEST DATA FROM
PATIENT REPORTED OUTCOMES AND
PATIENT-GENERATED HEALTH DATA
AND OTHER POPULATION DATA.
WE INGEST THE DATA AND WE
INTEND FOR IT TO BE USED BY
MULTIPLE STAKEHOLDERS TO ENHANCE
CLINICAL CARE.
THE ELECTRONIC HEALTH RECORD
SYSTEM IS INGESTED IN MORE THAN
ONE PARTICULAR PATHWAY.
THE MOST COMMON ONES ARE CALLED
OMOP AND FIRE AND A THIRD CALLED
API.
ONCE DATA IS ENTERED IN THE
INDIVIDUAL SITES SEE THEIR OWN
DATA IN A SITE SPECIFIC HUB
PORTAL AVAILABLE TO THOSE
INVESTIGATORS AND ONE LINE THAT
INCLUDES THEIR OWN DATA AND A
SECOND LINE THE AGGREGATE FOR
ALL THE INFORMATION ACCUMULATED
FROM ALL THE OTHER SITES.
TODAY THERE'S A TOTAL OF 51 SITE
ENROLLED IN THE DATA HUB.
THERE'S 15 IT MIRRORS THE
DISTRIBUTION OF WHERE SICKLE
CELL DISEASE S LIVE.
WE'RE JUST GETTING STARTED.
THIS IS AN EXAMPLE OF THE
INFORMATION THE MAJORITY ARE IN
URBAN CENTERS AND WE'RE PLEASED
AND PEDIATRIC AND ADULT PATIENTS
AND IN MANY INSTANCES SITES THAT
HAVE A COMBINATION OF BOTH ADULT
AND PEDIATRIC PATIENT.
WE HAVE TAKEN ON A ROBUST EFFORT
IN A SELECTED NUMBER OF SITES TO
USE INVESTIGATOR VERIFIED
DIAGNOSES AND THIS IS AN
INITIATIVE UNDERTAKEN TO ASK
SITES TO GO BACK AND VERIFY THE
DIAGNOSIS FOR PATIENTS SEEN IN
2022 AND DISTRIBUTION OF THE
PATIENTS THAT ARE NOW ALL
PATIENTS WHO HAVE A SINGLE
DIAGNOSIS NOT MULTIPLE SICKLE
CELL DISEASE DIAGNOSIS BUT THE
MOST SPECIFIC WE CAN.
TWO-THIRDS ARE SS AS MIGHT BE
EXPECTED.
ANOTHER QUARTER ARE SC AND
SMATTERING OF THE OTHER SICKLE
CELL VARIANTS.
WE THINK BY HAVING MORE
CERTAINTY WILL ALLOW US TO APPLY
OUR MEASURES OR OUR METHODS TO
ACTUALLY BEGIN TO COLLECT AND
STUDY MORE DATA THAT'S BEING
COLLECTED.
WHY LEARNING AND SICKLE CELL
DISEASE?
WE BELIEVE THIS KIND OF EFFORT
WILL IMPROVE PATIENT OUTCOMES ON
A NATIONWIDE BASIS AND ALLOW US
TO ADOPTION OF EVIDENCE-BASED
PRACTICES AND HOPE TO ESTABLISH
A NETWORK OF PROVIDERS TO
STANDARDIZE CARE ACROSS SICKLE
CELL CENTERS AND DEVELOP
LEADERS.
WE'VE ESTABLISHED A SET OF
MULTI-STAKEHOLDER TEAMS AT 15
PILOT SITES.
WE'VE ESTABLISHED COMMON GOALS
AND IMPROVEMENT AREAS AND FROM
THOSE CREATED CHANGE PACKAGES
AND WE'LL USE THE DATA FROM
PATIENTS IN THE DATA HUB TO
MEASURE CHANGE.
ASH HAD A VISION AND PARTNERED
TO GET US STARTED WITH THE FIRST
FEW AREAS TO BEGIN ENROLLMENT OF
THE SITES LOOK TO AT THE QI
CHANGE PACKAGES.
WE COMPLETE NED IMPLEMENTATION
AND ARE MOVING TOWARD THE
NATIONAL LAUNCH.
WE'VE CREATED A GLOBAL AIM TO
IMPROVE THE LIFE COURSE AND
QUALITY OF LIFE OF INDIVIDUALS
LIVING WITH SICKLE CELL DISEASE.
WE'VE RELIED ON INPUT FROM THE
COMMUNITY AS WELL AS OUR
INVESTIGATORS TO RANK A NUMBER
OF THEMES OR KEY DRIVERS AND
WE'VE BEGUN WORK ON THE FIRST
THREE.
SO JUST AS AN EXAMPLE THE
EFFECTIVE USE OF SAFE AND
EVIDENCE-BASED INFORMED
THERAPIES AND OUR FIRST AND MOST
DEVELOPED HAS BEEN TO INCREASE
THE RELIABLE USE OF DISEASE
MODIFIED THERAPIES INCLUDING
HYDROXY URIA AND INCREASE THE
USE OF OR DEVELOPMENT OF
CO-DEVELOPMENT OF PAIN
MANAGEMENT PLANS BETWEEN
PROVIDERS AND PATIENTS AND WE
JUST RECEIVED FUNDING LAST YEAR
TO BEGIN THE THIRD ONE WHICH IS
TO IMPROVE THE TRANSITION FROM
PEDIATRIC TO ADULT CARE.
>> I WANT TO TALK ABOUT CONDA
WHICH WE ARE SO EXCITED ABOUT
THE CONSORTIUM FOR NEWBORN
SCREENING IN AFRICA.
THIS BEGAN IN 2019 AND IT'S TO
DEMONSTRATE THE LAB-BASED
NEWBORN SCREENING AND EARLY
INTERVENTION IN SEVEN
SUB-SAHARAN AFRICAN COUNTRIES
SCREENING BETWEEN 10,000 AND
16,000 BABIES EACH YEAR AND
IDENTIFY BABIES WITH SICKLE CELL
DISEASE YOU USING
LABORATORY-BASED METHODOLOGY AND
WE ALSO CHARGED EACH ONE OF OUR
PARTNERS TO WORK TO IDENTIFY
NATIONAL AND INTERNATIONAL
PARTNERS TO LOOK TOWARDS
SUSTAINABILITY OF THE PROGRAMS.
THE NEWBORN SCREENING AND IN
PARTNERSHIP WITH CLINICAL STAFF
AND LABORATORY BASED STAFF,
TRAINING NURSES AND THE NEWBORN
TRAINING ACTIVITIES IN LABOR AND
DELIVERY OTHER TIMES PRIMARY
CARE SITES OR IMMUNIZATION
CLINICS AND LOOKING AT THE
MECHANISM FOR DELIVERY OF THE
SAMPLES AND ENSURING QUALITY
IMPROVEMENT.
THE CARE IN SICKLE CELL CENTERS
AND CAN BE DONE AT OTHER CARE
SITES ENSURES PATIENTS HAVE
ACCESS TO EVIDENCE-BASED
MEASURES TO FOLIC ACID, AND
MALARIA PREVENTION AND HAVE BEEN
FOCUSSED ON OVER ALL HEALTH
MONITORING AND FAMILY EDUCATION
WITH ADDITIONAL FUNDING TO THE
SITES TO HELP WITH THAT.
AND LOOKING FOR THEM BEING SEEN
ON A REGULAR BASIS FOR
FOLLOW-UP.
THESE ARE SOME OF OUR RESULTS
TODAY.
WE SCREENED OVER 90,000 BABIES
IN SUB-SAHARAN AFRICA AND THE
NUMBER OF CHILDREN IDENTIFIED
WITH SICKLE CELL DISEASE AND
TRAIT ARE CONSISTENT WITH WHAT
WE BELIEVE TO BE THE GENETICS IN
THOSE AREAS PLUS THE BIRTH RATES
AND WE'VE BEEN ABLE TO GET THESE
CHILDREN INTO CARE TO BE GIVEN
PENICILLIN.
THE MOST COMMON SOURCE FOR
MALARIA IS FOLIC ACID AND
PNEUMOCOCCAL VACCINES AND BED
NETS.
WE'VE PLEASED WITH OUR
PARTNERSHIP WHO DONATED
EQUIPMENT TO COUNTRIES WHO DID
NOT OTHERWISE HAVE IT ON SITE.
THEY HELPED WITH TRAINING AND
RETRAINING.
THERE WAS A WE HAD A MAJOR
SUMMIT WHERE ALL THE INDIVIDUAL
COUNTRIES WITHIN CONSA AND
OTHERS CAME TOGETHER TO WORK IN
GHANA ON TECHNIQUES FOR THEIR
LABORATORIES AND TO CONNECT THEM
AS A NETWORK.
WE ALSO HAVE OPPORTUNITIES FOR
VIRTUAL CONSULTATIONS WITH SOME
OF THE MORE ADVANCED OR MORE
EXPERIENCED LABORATORIES IN
AFRICA.
AND THEN AGAIN WE HAD A
LABORATORY SUMMIT LAST MONTH
WHERE FOLKS GATHERED TO ACTUALLY
LEARN FOR THE FIRST TIME OR TO
REFRESH THEIR SKILLS.
WE RECEIVED A SECOND GRANT TO
LOOK AT HEALTH WORKFORCE
EDUCATION AND THIS IS ACTUALLY
ASKING EACH COUNTRY TO DEFINE
HOW THEY'D LIKE TO PROCEED WITH
THAT AND WE'RE LOOKING TOWARDS
EDUCATING HEALTH CARE PROVIDERS
AT THE PRIMARY LEVEL WHERE EVEN
THOUGH WE INITIALLY TARGETED
BIRTH HOSPITALS IN LARGE CITIES,
WE RECOGNIZE THERE'LL BE MANY
SICKLE CELL CHILDREN DIAGNOSED
AND TREATED AT PRIMARY SITES.
THE GOAL WOULD BE TO DEVELOP THE
NETWORK TO ENSURE CHILDREN AT
ALL LEVELS HAVE OPPORTUNITIES
FOR FOLLOW-UP CARE AND REFERRAL
AS A NEED.
ASH IS ALSO WORKING IN
COLLABORATION WITH OTHER
PARTNERS.
ONE IN PARTICULAR IS THE
INITIATIVE THROUGH THE NATIONAL
NCDI POVERTY NETWORK SICKLE IN
AFRICA PARTIAL FUND FROM THE NIH
AND OTHERS TO LEVERAGE THE
CAPACITY TO EXPAND SICKLE CELL
EFFORTS ACROSS SUB-SAHARAN
AFRICA.
SUSTAINABILITY IS OUR BIGGEST
CHALLENGE AND HAVING
PARTNERSHIPS WITH THESE
GOVERNMENTS IN THESE COUNTRIES
WILL BE CRITICAL.
SOME MOVED TOWARDS HAVING THEIR
NATIONAL PLANS BEING
INCORPORATED INTO THE PLANS FOR
THEIR COUNTRIES AND KENYA AND
UGANDA ARE PARTICULAR EXAMPLES
OF THAT.
WE'VE ALSO PARTNERED WITH PHARMA
IN PARTICULAR NOVARTIS WHICH HAS
BEEN HELPFUL IN LOOKING AT
OPPORTUNITIES TO HAVE LOW-COST
ACCESS TO HYDROXY UREA AND USING
AN ONLINE MOBILE APP BASED
PROGRAM.
WE PARTNERED WITH CIVIL
SOCIETIES AND MEDIA CAMPAIGNS
AND OTHER ORGANIZATIONS IN
COUNTRY.
MANY ARE FAMILIES OF PATIENTS OR
PATIENTS THEMSELVES PARTICULARLY
HELPFUL WITH GIVING US FEEDBACK
AND INCREASING AWARENESS.
WE'VE ALSO BEEN VERY PLEASED TO
BE ONE OF THE FOUNDING MEMBERS
OF THE WORLD COALITION ON SICKLE
CELL DISEASE LAUNCHED IN MAY AT
THE WORLD HEALTH ORGANIZATION
AND WE RECOGNIZE THE
SUSTAINABILITY EFFORTS WILL
REQUIRE FUNDING FROM DONOR
COUNTRIES AND WE'RE COMMITTED TO
WORKING WITH COUNTRIES AS WELL
AS INDUSTRY PARTNERS AS WELL AS
NONPROFITS TOWARDS A FOCUS ON
LOW AND MIDDLE INCOME COUNTRIES.
IN SUMMARY, I THINK THIS NURSE
FROM NIGERIA SUMMED IT UP SHE'S
EMPOWERED PARENTS WITH NOCK AND
SEEING THEM WORK TO UNDERSTAND
THE PLAN OF CARE AND DISEASE
PROCESS.
SO THIS IS AN EXAMPLE OF A
POTENTIAL FOR PARTNERSHIP
NATIONALLY AND GLOBALLY TO
ADVANCE SICKLE CELL DISEASE.
THANK YOU.
>> OUR NEXT TWO SPEAKERS ARE
GOING TO BE ONLINE.
THEY HAVE SENT PREPARED
PRESENTATIONS.
THE FIRST IS ISAAC ODAME THE
HEMATOLOGY SECTION HEAD DIVISION
OF HEMO AT HOSPITAL OF SICK
CHILDREN IN TORONTO AND DIRECTOR
OF PEDIATRIC HEMATOLOGY IN THE
DEPARTMENT OF MEDICINE AND PIED
PEDIATRICS AT UNIVERSITY OF
TORONTO.
AND PERHAPS MORE GERMANE TO THIS
TALK THE MEDICAL DIRECTOR OF THE
GLOBAL SICKLE CELL DISEASE
NETWORK FOR GLOBAL HEALTH AND
THAT IS BUILDING ENDURING
COLLABORATIONS BETWEEN CLINICIAN
SCIENTISTS WORLDWIDE TO FURTHER
RESEARCH AND ADVANCE CARE FOR
OUR PATIENTS WITH SICKLE CELL
DISEASE.
PARTICULARLY IN LMICs
SHOULDERING THE HEAVIEST BURDEN.
HIS PRESENTATION IS PRE RECORDED
SO WE WILL WATCH THAT NOW.
THANK YOU.
>> GOOD MORNING.
I'D LIKE TO THANK THE ORGANIZERS
OF THIS SICKLE CELL IN FOCUS
CONFERENCE FOR GIVING ME THE
OPPORTUNITY TO PARTICIPATE IN
THIS SESSION ON GLOBAL
INITIATIVES.
I'LL SPEAK TO YOU ON THE WORLD
COALITION ON SICKLE CELL
DISEASE.
EARLIER THIS YEAR IN LANCET
HEMATOLOGY PUBLISHED A REPORT ON
THE MORTALITY RATES AND THE
MORTALITY RATES AND ON THE RIGHT
ARE THE TOTAL SICKLE CELL
DISEASE MORTALITY RATE.
THE DIFFERENCE REFLECTS ICD
CODING WHICH REQUIRES ONE
ATTRIBUTED TO ONE DEATH THE
CAUSE SPECIFIC MORTALITY RATE
AND THIS UNDERRATES DEATHS TO
WHICH SICKLE CELL DISEASE COULD
BE ATTRIBUTED AS A CONTRIBUTING
FACTOR.
TAKING MORTALITY RATES INTO
CONSIDERATION THE MAP SHOWS
SUB-SAHARAN AFRICA AND INDIA
SOUTH CONTINENT.
THE TRENDS IN MORTALITY RATE
FROM 2000 TO 2020 THOSE
INTERESTING TRENDS.
THE COLOR CODING HERE REPRESENTS
REGIONS OF THE WORLD.
AND ON THE LEFT IT'S SHOWING A
PERCENTAGE OF SICKLE CELL
DISEASE MORTALITY AS A PERCENT
AND OF OTHER CAUSES OF
MORTALITY.
THIS IS CAUSE-SPECIFIC MORTALITY
AND TOTAL MORTALITY.
OVER THE YEARS YOU CAN SEE THE
SUB-SAHARAN AFRICA EMERGES AS
THE AREA WHERE MORTALITY FROM
SICKLE CELL DISEASE HAS
INCREASED NOT ONLY FOR THE UNDER
5 AGE GROUP BUT ACTUALLY EVEN
HIGHER FOR THOSE UNDER 20 AND
CONTINUES TO 15 AND SAME IN
TOTAL MORTALITY RATE AND AREAS
LIKE INDIA EMERGE AS HAVING
INCREASE IN TOTAL SICKLE CELL
DISEASE MORTALITY.
IN TERMS OF MORTALITY RATES IN
POPULATION OVER TO 2020
SUB-SAHARAN INFRASTRUCTURE IS
SIGNIFICANT UNDER 5 MORTALITY
THOUGH THERE'S A TREND DOWNWARDS
OVER THE PERIOD IT STILL REMAINS
SIGNIFICANTLY HIGH IN CONTRAST
TO OTHER REGIONS OF THE WORLD.
THEREFORE, SICKLE CELL DISEASE
MORTALITY IS REALLY IMPACTING
DEVELOPMENT GOALS.
INCIDENT RATES REMAIN THE SAME
OVER THE PERIOD BUT THE PAIRS OF
SICKLE CELL DISEASE INCREASED
14% TO GREATER THAN 500,000 PER
YEAR AND THIS IS CONTRIBUTED
MAINLY TO POPULATION GROWTH IN
SUB-SAHARAN AFRICA AND IN THE
CARIBBEAN.
THEREFORE TOTAL SICKLE CELL
DISEASE MORTALITY RATES ARE TEN
TIMES HIGHER THAN CAUSE SPECIFIC
DEATHS.
IN TERMS OF UNDER 5 MORTALITY,
SICKLE CELL DISEASE MORTALITY
RUNS ACROSS ALL CAUSES AND WHEN
YOU TAKE SUB-SAHARAN AFRICA INTO
CONSIDERATION IT RANKS 11th
AHEAD OF MEASLES AND
MALNUTRITION.
THIS REFLECTS MATERNAL MORTALITY
AND 3.2 AND AIM TO PREVENTIBLE
DEATHS UNDER 5 YEARS OF AGE AND
3.4 TO PREVENT PREMATURE DEATH
FROM LUNG COMMUNICABLE DISEASES
WILL NOT BE MET WITHOUT
COMPREHENSIVE STRATEGIES TO
ADDRESS SICKLE CELL DISEASE.
THEREFORE SICKLE CELL DISEASE
REMAINS AN IMPERATIVE.
WHY IS MORTALITY HIGH IN
LOW-MIDDLE INCOME COUNTRIES AND
LACK OF SCREENING AND LACK OF
INTERVENTIONS LIKE HYDROXY UREA
THERAPY AS AFFORDABLE, FEASIBLE.
THIS IS A THERAPY AND POOR
ACCESS TO BLOOD TRANSFUSION,
HEALTH CARE INFRASTRUCTURE SO
ACCESS TO CARE IS NOT EVENLY
DISTRIBUTED ACROSS THE COUNTRY.
THERE'S LACK OF UNIVERSAL HEALTH
COVERAGE WHICH MEANS MANY
FAMILIES CANNOT AFFORD THE COST
OF CARE, TRAINING OF HEALTH CARE
WORKERS IS LACKING SO THE
EXPERTISE IS NOT EVENLY
DISTRIBUTED ACROSS THE COUNTRY
AND THE CASES FOR SICKLE CELL
DISEASE IS WEAK AND ABOVE ALL
GOVERNMENTS IN THIS PART OF THE
WORLD LACK THE POLITICAL WILL TO
ACT.
THE HIGH BARRIERS ARE TWOFOLD
SUPPORTING ANY OF THE
INTERVENTION THAT WE KNOW AND
REDUCE AND WHERE IMPLEMENTATION
IS TAKING PLACE THERE'S
INADEQUATE FUNDING TO SUSTAIN
THE PROGRAMS AND THE SCALING OF
PROGRAMS FOR COUNTRY WIDE REACH
WHICH IS WHY WE NEED THE
COALITION ON SICKLE CELL
DISEASE.
WHAT IS IT?
AN NATIONAL PUBLIC-PRIVATE
PARTNERSHIP INVOLVING ACADEMIC
SOCIETIES, PATIENT ORGANIZATIONS
AND FINANCIAL INSTITUTIONS,
INDUSTRY, THE PRIVATE AND PUBLIC
SECTOR AND THE GLOBAL FOCAL
POINT TO ADDRESS SICKLE CELL
DISEASE IN LOW AND MIDDLE INCOME
COUNTRIES.
IT WAS WORLDED THE WORLD HEALTH
ORGANIZATION AND WORLD BANK AND
THE U.S. DEPARTMENT OF HEALTH IN
2020 AND AIMS TO ENHANCE
COORDINATION IN THE IMPAIRED
COUNTRIES.
THIS YEAR IN MAY THE WORLD
HEALTH ASSEMBLY IN GENEVA THE
COALITION WAS LAUNCHED AND HAS
BECOME THE PLATFORM TO ADDRESS
SICKLE CELL DISEASE.
THE MISSION IS TO BE THE LEADING
GLOBAL ORGANIZATION ACTING AS
THE TRUSTED VOICE FOR SICKLE
CELL DISEASE COMMUNITY TOGETHER
AND NOT IN ISOLATION BUT IN
COLLABORATION WITH PARTNERS.
THE COALITION WILL WORK TO
VASTLY REDUCE CHILDHOOD
MORTALITY ASSOCIATED WITH SICKLE
CELL DISEASE AND SIGNIFICANTLY
IMPROVE THE LIVES OF PEOPLE
LIVING WITH DISEASE IN LOW
MIDDLE INCOME COUNTRIES.
THE TIME LINE IS AS FOLLOWS.
THEY HAVE AREAS IN WASHINGTON,
D.C. AND AFTER THE PANDEMIC
STALLED THE PROGRESS BUT WAS
REACTIVATED IN PARIS IN JUNE
2022.
FOLLOWING THAT THERE'S BEEN
VIRTUAL MEETINGS ENGAGING
PARTNERS AND PROVIDING
INFORMATION ABOUT THE PROGRESS
OF THE COALITION IN SEPTEMBER
2022 AND IN MAY 2023 THE
COALITION WAS LAUNCHED IN GE
GENEVA.
IN TERMS OF REFERENCE HAVE BEEN
SET UP A COMMITTEE TRANSITIONING
INTO A BOARD.
PATIENT VOICE IS GOING TO BE
SYSTEMATICALLY ENGAGED TO REMAIN
AS CENTRAL AND IMPORTANT PART OF
THE COALITION AS THE COALITION
IS INTENDED TO ADDRESS THE NEEDS
OF PATIENTS AND THEREFORE THEIR
VOICE HAS TO BE CENTRAL.
STRATEGY BUILDING IS GOING TO BE
CONTINUE IN THIS FALL LEADING US
TO THE COMING YEAR AND BEYOND.
THE STEERING COMMITTEE CURRENTLY
IS MADE UP OF REPRESENTATION IN
THE AFRICA SICKLE CELL
ORGANIZATION BASED IN KENYA.
AMERICAN SOCIETY OF HEMATOLOGY.
THE GLOBAL SICKLE CELL DISEASE
NETWORK THE PFR FOUNDATION WHICH
HAS MADE A FOOTPRINT IN
INFRASTRUCTURE AND THE WORLD
HEALTH ORGANIZATION AND INDUSTRY
PARTNERS PFIZER AND NOVARTIS AND
OTHERS.
THE COALITION HAS IDENTIFIED
FIVE PRIORITIES FOR ACTION AND
TO ORGANIZE ITS WORK IN FIVE
PILLARS FROM THE PERIOD 2024 TO
2025.
FIRST, TO SCALE UP NEWBORN
SCREENING IN INFANTS' DIAGNOSIS
AND EARLY DIAGNOSIS IN THESE
REGIONS.
TO INTEGRATE SICKLE CELL DISEASE
MANAGEMENT INTO PRIMARY CARE AND
MAKE IT ACCESSIBLE AROUND ALL
HEALTH SYSTEMS.
EXPAND ACCESS TO CARE AND ACCESS
TO HYDROXY UREA THERAPY AN
EFFECTIVE DISEASE MODIFYING
THERAPY WHICH IS FEASIBLE AND
IMPLEMENTABLE AND MAKE SURE
ADEQUATE RESOURCES ARE PROVIDED
FOR SICKLE CELL DISEASE
PROGRAMMING AND TO SUPPORT
RESEARCH PARTICULARLY TO COLLECT
RELIABLE DATA THAT REFLECTS
TRAINING EVALUATION OF THE
PROGRAM AND IMPROVE QUALITY OF
LIFE.
FIRST IS POLICY.
SECOND IS STAKEHOLDER ENGAGEMENT
AND OPERATIONS.
AND POLICY ASK AND OUTLINE A
SHARED POLICY NARRATIVE TO
BECOME THE BASIS FOR ADVOCACY
BOTH NATIONALLY AND GLOBALLY.
PROMOTE THE ADOPTION AND UPDATE
OF PLANS SUBMITTED TO FINANCIAL
INSTITUTIONS LIKE THE WORLD BANK
FOR FINANCING AND SUPPORT.
LOOKING AT TO ADVOCATE FOR THE
NEEDS OF INDIVIDUALS WITH
DEVELOPED AND ADVOCACY WILL BE A
FOCUS BY LEVERAGING CONGRESSES
AND EVENTS AS MILESTONE MOMENTS
THROUGHOUT THE YEAR TO SUPPORT
EFFORTS AND MOBILIZATION WILL BE
THAT WILL PROACTIVE SEEK
OPPORTUNITIES TO DO AND SECURE
AND SUPPORT FOR THE COALITION
AND COMMITMENT FROM FUNDERS ON
OUR PROGRAMMATIC WORK AND ENSURE
ADEQUATE MANAGEMENT, PROJECT
PLANNING AND IMPLEMENTATION AND
ALSO AND CONTINUOUS IMPROVEMENT
OF THE COALITION MEMBERSHIP IS
GOING TO BE ORGANIZED IN A
TIERED STRUCTURE BEGIN.
THE FULL MEMBERS WILL HAVE EARLY
ACCESS TO EVENTS INVITATIONS AND
PARTICIPATING IN COALITION
MEETINGS AND SHAPING POLICY AND
BEING PART OF WORKING STREAMS
THAT DISCUSS STRATEGY FOR THE
COALITION.
PREMIUM MEMBERS ARE GOING TO BE
ABLE TO HAVE FULL MEMBERSHIP AND
DRAW ON THE PRIVILEGES OF FULL
MEMBERSHIP BUT IN ADDITION BE
ABLE TO SET AGENDA FOR EVENTS
AND BE ABLE TO BE PART OF
STRATEGY COMMITTEES THAT WILL BE
DEVELOPING STRATEGY FOR THE
COALITION.
AND THE ANNUAL FEEDS ARE SHOWN
THERE 25K FOR AFFILIATE MEMBERS,
50K FOR FULL MEMBERS AND 100K
FOR PREMIUM MEMBERS.
PLEASE JOIN US.
WE'RE LOOKING FOR PASSIONATE
STAKEHOLDERS AND PARTNERS AND
COLLABORATORS FROM ALL SECTORS
AND FINANCIAL INSTITUTIONS AND
ACADEMICS SOCIETIES AND
INSTITUTIONS.
PLEASE CONTACT ANDREW ZAPFEL AND
PETER VARNUM BASED IN GENEVA.
LET ME ALSO TAKE THIS
OPPORTUNITY TO INVITE YOU TO
BLOCK THE DAYS JUNE 3 TO THE
JUNE 5 FOR THE GLOBAL CONGRESS
ON SICKLE CELL DISEASE AND THIS
IS GOVERNMENTAL AND
NON-GOVERNMENTAL AND
INTERNATIONAL PARTNERS AND THE
GLOBAL SICKLE CELL DISEASE
NETWORK HELD IN ABUJA THE CAL
WITH THE HIGHEST BURDEN OF
SICKLE CELL DISEASE.
WE HOPE TO BE ABLE TO BRING YOU
PROGRESS THAT THIS COALITION HAS
MADE AS A COLLABORATION AND
PARTNERSHIP THAT IS AIMED AT
VASTLY REDUCING SICKLE CELL
DISEASE MORTALITY AND IMPROVING
THE QUALITY OF LIFE OF PEOPLE
LIVING WITH SICKLE CELL DISEASE
AND WITH THAT I WANT TO SAY
THANK YOU VERY MUCH FOR
LISTENING.
>> WONDERFUL.
WE'RE GOING TO MOVE ON TO THE
NEXT SPEAKER BECAUSE DR. ODAME
IS NOT AVAILABLE TO ANSWER
QUESTIONS.
THE NEXT TALK WILL BE BY
DR. MARIE DOMINIQUE
HARDY-DESSOURCES WHO WORKED AT
FRENCH NATIONAL INSTITUTE OF
HEALTH AND MEDICAL RESEARCH FOR
MORE THAN 30 YEARS.
SHE'S BEEN INTERESTED IN SICKLE
CELL DISEASE SINCE HER Ph.D. AND
HELPED CREATE THE FIRST FRENCH
SICKLE CELL CENTER.
MARIE-DOMINIQUE IS A FOUNDING
MEMBER OF THE CARIBBEAN NETWORK
FOR RESEARCH IN SICKLE CELL
DISEASE IN PARIS WHICH IS AN
UNUSUAL ENTITY.
IN THE CARIBBEAN IT'S THE ONLY
ONE I KNOW WHERE WE HAVE FRENCH,
SPANISH AND ENGLISH SPEAKING
MEMBERS WHO WORK TOGETHER.
SHE'S BEEN PRESIDENT OF THE
BOARD OF DIRECTORS OF THIS
NETWORK SINCE ITS INCEPTION IN
2012 AND AS I SAID, HER TALK IS
GOING TO BE VIRTUAL BUT AT THE
END IF THERE ARE ANY QUESTIONS
I'LL TAKE THEM BECAUSE I'M THE
VICE PRESIDENT.
>> GOOD MORNING.
I'M MARIE-DOMINIQUE
HARDY-DESSOURCES AND REPORTING
ON AN INITIATIVE NET TO IMPROVE
THE LIVES OF PEOPLE WITH SICKLE
CELL DISEASE IN OUR CARIBBEAN
NATION.
CAREST HAS 10 YEARS OF
EXPERIENCE AND WE CAN LOOK BACK
AT THE RESEARCH OVER 10 YEARS
AND ANALYZE THEIR IMPACT.
BUT LET ME REMIND YOU THAT THE
CARIBBEAN IS A GROUP OF STATES
AND TERRITORIES BOTH ISLANDS AND
CONTINENTS AS SHOWN IN THE
SLIDE.
THEY SHARE A COMMON HISTORY AND
CULTURE AND GEOGRAPHY BUT
DIVERSITY OF LANGUAGE AND
GOVERNMENTS AND ECONOMIES.
AND IN THIS CONTEXT, THE DISEASE
IS A BURDEN AND SHARE SICKLE
CELL DISEASE GENE.
THE LAST OBSERVATION LED TO THE
SETTING UP OF THE CAREST NETWORK
AS DEDICATED TO COOPERATION.
THUS IN FEBRUARY 2012, THE
CAREST NETWORK WAS FORMALLY
ESTABLISHED AS A NON-PROFIT
ORGANIZATION TO MEET A CLEAR
NEED FOR COLLABORATION AMONG
PRACTITIONERS TO WORK TOGETHER
TO IMPROVE THE LIVES OF PEOPLE
WITH SICKLE CELL DISEASE THROUGH
RESEARCH, EDUCATION AND CLINICAL
CARE TO PROMOTE EARLY DIAGNOSIS
FOR NEWBORN SCREENING,
COLLABORATION ON RESEARCH
PRIORITIES TO CONDUCT CAMPAIGNS
TO PROMOTE THE RECOGNITION AS
PUBLIC HEALTH PRIORITIES.
LET US LOOK AT THE AREAS AND
FIRST AT THE RESEARCH FOR ACCESS
TO NEWBORN SCREENING.
THE BLUE INDICATES COUNTRIES AND
TERRITORIES THAT HAVE ACCESS TO
SCREENING BEFORE CAREST.
JAMAICA, FRENCH GUYANA AND
MARTINIQUE AND CUBA.
THE GREEN COLUMN REPRESENT
COUNTRIES THAT HAVE GAINED
ACCESS TO NEWBORN SCREENING WITH
THE SUPPORT OF CAREST.
IN JAMAICA, THE GREEN COLOR IN
ADDITION TO THE BLUE INDICATES
THE NEWBORN SCREENING WAS IN
PLACE BUT HAS BEEN STRENGTHENED
WITH THE SUPPORT AND INCLUDING
THE SICKLE CELL DISEASE ANEMIA
ASSOCIATION OF JAMAICA AND THE
CARIBBEAN INITIATIVE.
AND SCREENING COVERAGE INCREASED
FROM 30% TO 100% FROM 2015 WITH
THIS COLLABORATIVE SUPPORT.
FINALLY, THE YELLOW COVERS
INDICATE THE SCREENING PROGRAMS
WITH THE SUPPORT OF PARTNERS
OTHER THAN CAREST OTHER
LOCATIONS.
THE GREEN COLOR FOR HAITI IN
ADDITION TO THE YELLOW ONE
INDICATES THAT CAREST HAS
CONTRIBUTED CLINICIANS IN THE
SCREENING TECHNIQUES.
WE HAVE COMPARED ALL THE DATA
INCLUDING IN COSTA RICA AND
COLOMBIA AND THE DATA IN
NEONATAL SCREENING IN 2019.
IN ORDER TO PROVIDE ACCESS TO
NEWBORN SCREENING FOR SICKLE
CELL DISEASE IN THE CARIBBEAN
AND UPDATE OF THE PREVALENCE OF
THE DISEASE.
THANKS TO THE SCREENING PROGRAM
YOU CAN SEE THE PREVALENCE OF
DISEASE VARIES ACROSS THE
CARIBBEAN WITH JAMAICA AND CUBA.
THANKS TO THE SCREENING PROGRAM
IT'S ALSO BEEN ABLE TO PUBLISH
ITS FIRST DATA IN THE JOURNAL OF
MEDICAL SCREENING SHOWING SICKLE
CELL DISEASE WAS DIAGNOSED FOR 1
IN 150 NEWBORNS AND RECENTLY
ANTIGUA WAS ABLE TO TO HAVE DATA
PUBLISHED THIS YEAR IN THE
INTERNATIONAL JOURNAL OF KNEW
KNEWO -- NEONATAL DISEASE IT'S
DIAGNOSED IN 1 IN 222 NEWBORNS.
LET US LOOK AT THE IMPACT OF
CAREST ON RESEARCH.
RESEARCH HAS BEEN CONDUCTED BY
USING THIS IN JAMAICA AND OTHER
LOCATIONS AND EXPLORING THE
SICKLE CELL DISEASE SEVERITY AND
TO INDICATE THE ON SET OF VASO
OCCLUSIVE CRISIS.
THE STUDIES HAVE SHOWN THAT VASE
YO OCCLUSIVE CRISIS ARE
ASSOCIATED WITH AN EXACERBATION
OF OXIDATIVE STRESS, REDUCE
LEVELS OF ANTIBODIES THAT MAY BE
RELATED TO THE OXIDATION OF
BLOOD CELLS.
THE STUDIES PROVIDED THE
OPPORTUNITY FOR TRAINING YOUNG
SCIENT
SCIENTISTS.
THEIR NAMES ARE SHOWN ON THE
SLIDE IN RED AND ONE OF THE
YOUNG SCIENTIST IS CURRENTLY
WORKING ON A PROJECT TO
FOLLOW-UP HIS WORK.
THE TITLE THE MICROPARTICLES OF
SICKLE CELL DURING CRISIS OR
TAKING HYDROXYUREA MODIFY
INFLAMMATORY PROPERTIES.
THE AIM OF THE NEW PROJECT IS TO
EVALUATE THE EFFECT OF
HYDROXYUREA ON MICROPARTICLES
AND RESISTANCE TO HYDROXYUREA IN
SICKLE CELL ANEMIA.
IT PROPOSES TO CARRY OUT THE
PROJECT AS PART OF THE
COLLABORATION INVOLVING, CUBA,
JA MACHA -- JAMAICA AND
MARTINIQUE AND IT'S A PART OF
THE PROGRAM TO SUPPORT THE
DISSEMINATION OF KNOWLEDGE ABOUT
SICKLE CELL DISEASE AND
THALASSEMIA ACHIEVED THROUGH
PROGRAMS.
THE PROGRAM FOR DOCTORS AND
NURSES AS WELL AS THE JAMAICAN
MEMBERS.
IN THIS WAY UPDATED CLINICAL
PROGRAMS AND WE HAVE ORGANIZED
REGULAR CONFIDENCES TO SHARE
ADVANCES UP CARE AND RESEARCH.
THE LAST ONE IN FRENCH GUYANA IN
2018.
WE PLAN TO RESUME THE CONFERENCE
CYCLE INTERRUPTED BY THE COVID
PANDEMIC.
SHARING EXPERTISE ON APPROPRIATE
TREATMENT TO MANAGE COMPLICATION
OF THE DISEASE IS A KEY
OBJECTIVE OF THIS KNOWLEDGE
TRANSFER.
HYDROXYUREA APPEARS TO BE THE
MOST COMMON INTERVENTION BUT
LAST YEAR WE FOUNDED A COMPANY
TO PROVIDE FREE HIYDROXYUREA TO
CHILDREN AND IT REMAINS
IMPRACTICAL IN MOST COUNTRIES
EXCEPT FOR THE FRENCH
TERRITORIES WHERE IT'S POSSIBLE.
BUYING LIMITS THE ACCESSIBILITY
OF HEMATOPOIETIC STEM CELL
TRANSFUSION EXCEPT FOR THOSE IN
THE FRENCH TERRITORIES.
PREVENTION IS ALSO IMPORTANT FOR
US INTRODUCED IN COUNTRIES WITH
A DEDICATED SICKLE CELL CENTER
AS WELL AS IN DOMINICAN REPUBLIC
AND COSTA RICA AND GIVEN THE
SUPPORT AND TRAINING IS PLANNED
FOR GRENADA WITH THE SUPPORT OF
THE UNIVERSITY OF HOSPITAL
GUADALUPE AND YOU CAN SEE ON THE
SLIDE AND WE HAVE LAUNCHED AN
ONLINE PLATFORM CALLED SCOPE AND
AS A DRIVING COURSE.
WE BELIEVE THIS PLATFORM CAN BE
USEFUL TOOL TO ARRANGE
STAKEHOLDER INCLUDING POLICY
MAKERS TO IDENTIFY BEST
PRACTICES TO IMPLEMENT AND
IDENTIFY AND ADVOCATE FOR
SIMILAR CARE FOR THEIR
COUNTRIES.
SO I HAVE TRIED TO BRIEFLY
PRESENT THE CAREST 10 YEARS OF
ACTIVITY AND SPIRIT IN WHICH
THEY HAVE BEEN CARRIED OUT.
IT'S IMPORTANT TO SAY THIS
ACTIVITY IS DRIVEN BY A BOARD OF
DIRECTORS MADE UP OF DIFFERENT
MEMBERS OF THE CARIBBEAN AS
INDICATED BY THE ICONS AND THE
SLIDE.
WE CAN SEE LOOKING BACK 10 YEARS
IN ORDER TO CONTRIBUTE TO BE
EFFECTIVE IN IMPROVING THE LIVES
OF PEOPLE WITH SICKLE CELL
DISEASE IN OUR REGION, IT IS
IMPORTANT TO HAVE AN ASSOCIATION
WHICH PLAY A KEY ROLE WHERE
THERE IS NOT YET A SICKLE CELL
CLINIC.
WE ALSO CALL ON THE YOUNGER
GENERATION TRAINED BY US TO PLAY
THEIR FULL PART IN CONTINUING.
SO I THANK YOU FOR YOUR KIND
ATTENTION.
>> THANK YOU.
SO WE'RE ACTUALLY RUNNING ON
TIME.
AGAIN, WE HAVE TIME FOR ONE
QUESTION IF SOMEBODY HAS ONE.
IF NOT I'M NOT SEEING ANYTHING
HERE EITHER.
THANK YOU FOR YOUR ATTENTION
DURING THIS SESSION AND I'M
GOING HANDLE IT TO DR
DR. WEST-MITCHELL.
>> GOOD MORNING, EVERYONE.
WE'LL START SESSION 2 FOCUSSED
ON BLOOD TRANSFUSION.
OUR FIRST SPEAKER IS DR. SEAN
STOWELL WHO'S TALK HAS BEEN
RECORDED.
I'LL INTRODUCE DR. STOWELL THE
DIRECTOR OF THE NATIONAL CENTER
OF FUNCTIONAL DICOMICS.
-- GLYCOMICS AT HARVARD MEDICAL
SCHOOL AND HE RUNS A RESEARCH
PROGRAM AT BRIGHAM AND WILLIAMS
AND GOT TRAINING IN LABORATORY
AND TRANSFUSION MEDICINE.
HIS PRESENTATION IS PRERECORDED
SO WE'RE ABOUT TO START.
>> I WANT TO THANK SWEE, JOHN,
JENNIFER AND MONIKA FOR
ORGANIZATION OF ORGANIZING AND
INVITING ME TO TALK ABOUT MY
WORK IN WORKING WITH PATIENTS
WITH SICKLE CELL DISEASE AND I
THOUGHT I'D EMPHASIZE SOME OF
THE SPECIFIC TRANSFUSION
COMPLICATIONS PATIENTS WITH
SICKLE CELL DISEASE AND SOME
CHALLENGES THE COMPLICATIONS CAN
RESULT IN IN SEEKING TO
TRANSFUSE OR NOT TRANSFUSE.
I APOLOGIZE I CAN'T BE THERE.
I AGREED TO SPEAK IN SENEGAL,
AFRICA OTHERWISE I'D LOVE TO BE
THERE.
I'M GOING TO START WITH A CASE I
EXPERIENCED AS A RESIDENT THAT
INFLUENCED BY DESIRE TO STUDY
TRANSFUSION IN PARTICULAR IN
SICKLE CELL DISEASE IN GENERAL.
AND THE COMPLICATION THAT
RESULTS.
THIS A GENTLEMAN WITH SICKLE
CELL DISEASE PRESENTING AND HE
HAD MANY ANTIBIOTICS AND AT TIME
OF PRESENTATION RECORDS
INDICATED AN ANTI-S.
HIS BASELINE HEMOGLOBIN WAS 5.
A QUESTION WE HAD WAS HOW MANY
UNITS SHOULD WE GIVE FOR THE
PARTICULAR TRANSFUSION WITH THE
COMPLICATED HISTORY.
IF YOU WERE PRESENTED WITH THE
PATIENT HOW MANY UNITS WOULD YOU
PROCURE PRIOR TO SURGERY?
4, 5, 14, 17, JUST WALK THROUGH
THE CASE WITH ME AS I PRESENT.
WE DECIDED TO GIVE 7 UNITS.
IT TOOK ABOUT 6 WEEKS AND
TRANSFUSED BY THOSE UNITS AND
FOUND TO HAVE A HEMOGLOBIN CLOSE
TO 10 AND HE WAS THOUGHT TO BE
READY TO UNDER GO SURGERY.
THE SURGERY WAS UNEVENT.
.
TO BLEEDING EVENT OR ADDITIONAL
TRANSFUSION REQUIRED BUT HE
BECAME UNSTABLE AND WHAT WOULD
YOU DO IN THE SITUATION?
YOU HAVE TO FIGURE OUT POTENTIAL
SOURCE OF BLEEDING.
TRANSFUSE ONE UNIT OR GIVE RED
CELL SUBSTITUTES?
THE PATIENT WAS IMMEDIATELY
TAKEN BACK TO THE O.R. AND GIVEN
TWO UNITS ON THE WAY BECAUSE OF
HIS INSTABILITY.
IT WAS FOUND HE HAD THE
HEMOGLOBIN DOWN TO 5.7.
HE WAS TRANSFERRED TO THE ICU
AND ADDITIONAL UNITS WERE ORDERS
BECAUSE WE EXHAUSTED OUR
NATIONAL SUPPLY AND THE NEXT 24
HOURS THE PATIENT ALSO HAD A
HISTORY OF SEVERAL TRANSFUSION
REACTIONS AND WE WERE NERVOUS TO
TRANSFUSE HIM ANYTHING LESS THAN
FULLY COMPATIBLE AFTER 24 HOURS
HIS ONE UNIT WAS S POSITIVE AND
ONE E POSITIVE AND THE PATIENT
WE DID A CROSS MATCH AND THE S
POS UNIT WAS COMPATIBLE
PRESUMING THE ANTI-S WAS NOT
SHOWING AT THE TIME.
SO WHAT WOULD DO YOU IN THE
SITUATION?
WOULD YOU WITHHOLD TRANSFUSION
AND HOPE TO TURN IT AROUND AND
GIVE THE V POSITIVE OR S
POSITIVE ONLY OR BOTH UNITS OR
USE A BLOOD SUBSTITUTE?
AND THERE WERE ACCUSE ADVERSE
EVENTS.
POST HEMOGLOBIN WAS 5.4 AND THE
PATIENTS LABORATORY VALUES AND
CLINICAL STATS BEGIN TO
STABILIZE.
HE WAS GIVEN STEROIDS DURING THE
COURSE.
TWO ADDITIONAL UNITS BECAME
VALUABLE POST-OP DAY FOUR AND
SEVEN DAYS FOLLOWING TRANSFUSION
OR SURGERY HE HAD STABILIZED AND
HAD A HEMOGLOBIN 7.1 AND
TRANSFERRED FROM THE ICU TO THE
FOR.
FOR POST-OP DAY NINE HE WAS
POSITIVE FOR IHG AND BILIRUBIN
BEGAN TO INCREASE.
SO WHAT WE THINK IS GOING ON IS
THIS AN ADDITIONAL SURGICAL
BLEED, POTENTIAL DEVELOPMENT OF
A SICKLE CELL COMPLICATION DUE
TO UNDERLYING DISEASE, A DELAYED
REACTION OR HYPERHEMOLYSIS AND
IN TERM OF ICG IT WAS IMPORTANT
AND IN CONJUNCTION HIS ANTI-S
WENT FROM A 0 TO 4+ AND THERE
WAS A TRANSFUSED REACTION AND BY
POST-ON DAY 13 HIS HEMOGLOBIN
2.9 AND WHY IS IT CONTINUING TO
DECLINE BEYOND?
WAS HE DEVELOPING A SURGICAL
BLEED?
HAVING AN SICKLE CELL
COMPLICATION?
DELAYED REACTION OR POSSIBLE
HYPERHEMOLYSIS.
THERE'S NO EVIDENCE OF BLEED ON
EXAM OR IMAGING AND WAS
TRANSFERRED BACK TO ICU, POST-OP
DAY 15, TWO UNITS WERE FINALLY
IDENTIFIED BUT BY THE TIME THEY
WERE READY TO TRANSFUSED HE
UNFORTUNATELY DEVELOPED SIGNS OF
MULTI-ORGAN INJURY AND
UNFORTUNATELY REGRESSED TO ORGAN
FAILURE AND SUCCUMB ON POST-OP
DAY 17.
THIS WAS A DEVASTATING OUTCOME
AS A RESULT OF TRANSFUSION
COMPLICATION IN THESE PATIENTS
AND THE ABILITY TO PROCESS THE
BLOOD IN A TIMELY FASHION.
ANTIBODIES CAN CAUSE THESE TYPES
OF TRANSFUSION REACTIONS.
AT EMORY WE WOULD SEE FIVE OR
SIX OF THESE TYPES OF CASES
EVERY YEAR FOR OUR ABILITY TO
TRANSFUSE OR COMPLICATIONS.
THIS WAS A SIGNIFICANT MOTIVATOR
FOR ME PERSONALLY TO TRY TO
UNDERSTAND NOT ONLY THE
DEVELOPMENT OF THE ANTIBODIES
BUT WITH THE CONSEQUENCE OF THE
ANTIBODIES ONCE DEVELOPED IN THE
TRANSFUSION SETTING FROM THE
PATIENTS JUST NEED A SIMPLE
TRANSFUSION.
WHAT REGULATES ADVERSE OUTCOMES
OF TRANSFUSION WITH ANTIBODIES?
WE THINK IT'S AN IMPORTANT THING
TO STUDY.
THERE'S BEEN WORK ON THE
DEVELOPMENT OF ANTIBODIES AND
WORK BY OUR OWN GROUP AND 30% TO
40% OF PATIENTS PREVENTIVE
STRATEGIES WON'T BE SUPER USEFUL
AND WE TRY TO PREVENT THESE
FORMATIONS AND THE BLOOD IS
STILL A SIGNIFICANT PROBLEM IN
THESE PATIENTS.
I THINK THIS MAY CONTRIBUTE TO
WHAT WAS PUBLISHED ABOUT EIGHT
YEARS AGO NOW DEMONSTRATING THAT
PATIENTS HAD A HIGHER MORTALITY
RATE THAN OTHERS THAT WERE NOT
AND THERE'S A HYPOTHESIS THAT
PEOPLE WHO ARE ALOE IMMUNIZED
AND CAN BE IMPACTED AND THE
CELLS MAY BE POESH AS WELL.
-- IMPORTANT AS WELL AND IT'S
UNCOMMON FOR PATIENTS TO GET THE
TRANSFUSION RESULTING IN AN
ACUTE REACTIONS BUT THE REASON
THEY'RE PROBLEMATIC IS AS
FOLLOWS WHEN THE PATIENT
DEVELOPED A PRIMARY RESPONSE
WITH THE FIRST EXPOSURE TO THE
ANTIGEN AND THE AMBULATORY
RESPONSE CAN ARE OFTEN NOT LONG
LIVED ABOUT 50% TO 60% IN SOME
STUDIES CAN GO TO LEVELS
UNDETECTABLE CLINICALLY EITHER
IT'S NOT EITHER DETECTED BY ANY
HEALTH CARE SYSTEM BECAUSE THEY
DON'T ROUTINELY EVALUATE OR WAS
DETECTED WHEN A PATIENT SEEKS A
DIFFERENT HEALTH CARE SYSTEM AND
BECAUSE THERE'S NO NATURALIZED
SYSTEM TO COUNT THE ANTIBODIES
THERE'S NO WAY TO LOOK IF THE
PATIENT MADE ANTIBODIES AGAINST
ANY PARTICULAR ANTIGEN.
THAT HAPPENS WHEN PATIENTS GET
REEXPOSED TO AN ANTIGEN THEY
PREVIOUSLY MADE AN RESPONSE TO
AND IT CAN TRANSFUSE THE
HEMOGLOBIN A AND SOME PATIENTS
NOT ONLY CAN EXPERIENCE THE H
HEMOLYSIS IN THEIR OWN RED CELLS
AND FIRST THE DELAYED REACTION
AND THIS CASE WAS RECORDED IN
1962 OUT OF WASH-U AND WAS AN
EXAMPLE OF HYPERHEMOLYSIS AND
OUTLINED A FEATURE I DIDN'T
APPRECIATE WHERE THEY CAN OCCUR
IN THE ABSENCE OF ANTIBIOTIC.
I JUST DESCRIBED THE ROLE OF
ANTIBODIES IN THESE BUT IT CAN
RESULT IN CLEARANCE TO THE UNIT
AND HYPERHEMOLYSIS AND THEY
DON'T HAVE AN ANTIGEN AND IT'S
USUALLY DETECTED USING A SEGMENT
OF THE RED CELL AND COULD BE
THERE'S A PROCESS AT PLAY.
THESE ARE THOUGHT TO BE RARE 1
IN 1,000 TRANSFUSION AND THERE
WAS A STUDY LOOKING AT REACTION
FAIL AND MANY WERE NOT DIAGNOSED
AT THE TIME OR DETECTED OR
RECOGNIZED LATER ON AND THAT MAY
BE DUE TO THE FACT THAT A LOT OF
TIMES THESE PATIENTS PRESENT ONE
OR TWO OR THREE WEEKS AFTER THE
EVENT AND ONCE AGAIN MAY PRESENT
TO A DIFFERENT HEALTH CARE
FACILITY OR IT'S NOT KNOWN TO
THAT PROVIDER AND WHEN THEY
PRESENT IT CAN LOOK LIKE
UNDERLYING COMPLICATIONS OF THE
PATIENTS LIKE VASO OCCLUSIVE
CRISIS AND UNDERSTANDABLE IN THE
BLOOD BANK AND EVEN IF THE WORK
UP IS DONE IT MAY NOT BE
DETECTED.
RECOGNIZING THIS POTENTIAL
PROBLEM WITH ASSESSING WHEN THE
REACTIONS THAT OCCUR AND A STUDY
FROM PARIS LOOKED AT HEMOGLOBIN
MEASUREMENTS POST TRANSFUSION
AND WHEN THE PATIENT
RE-PRESENTED IN WEEKS AND THE 4%
TO 3% OF ALL EPISODIC
TRANSFUSIONS RESULTED IN THE HGR
AND 11% SUCCUMBED.
THESE REACTIONS ARE MORE FROEKT
AND DIFFICULT IN RESULTING IN
MORTALITY.
WE THINK OF TRANSFUSION
REACTIONS IN GENERAL WHICH IS
NOT ANY DIFFERENT IN THE SICKLE
CELL POPULATION YOU THINK OF
LARGER REACTIONS IN TRANSFUSION
AND COMMON TRANSFUSION REACTIONS
AND THEY'RE MORE OF A NUISANCE
AND IN THE KNOWN TO CAUSE
LONG-TERM ISSUES AND WE RECORDED
THEM FOLLOWING A TRANSFUSION OR
DURING A TRANSFUSION AND ONCE
AGAIN NOT SUPER COMMON BUT IN
THE FRENCH COHORT THESE
REACTIONS WERE THE MOST COMMON
BY A LONG SHOT AND NOT ONLY THE
MOST COMMON BUT AGAIN DEADLY.
THESE RESULTS SUGGEST PERHAPS WE
NEED TO BE MORE AWARE OF THE
REACTION AT LEAST I FEEL LIKE I
NEED TO BE MORE AWARE OF THE
REACTIONS NOT ONLY IN TERMS OF
BEING ABLE TO DIAGNOSE THEM AND
RECOGNIZE THE FEATURES THAT MAY
CONTRIBUTE TO THE
PATHOPHYSIOLOGY AND TREAT THEM
WHEN THEY OCCUR.
HEMOLYSIS CAN ALTER THE PATHWAY
AND WE LOOKED AT THE ACTIVATION
AND DHTRs AND MANY PATIENTS
DISPLAYED ACTIVATION OF
COMPLIMENT SUGGESTING A
COMPLEMENT MAY BE INVOLVED AND
TO STUDY THIS IN SICKLE CELL
COMPILATION AND WE CONDUCTED A
STUDY IN PATIENTS LOOKING AT
PATIENTS WITH ACUTE CHEST AND
DEVELOPING ACUTE CHEST SYNDROME
AT BASELINE WEEKS LATER TO
DETERMINE THE INCREASE IN SICKLE
CELL COMPLICATION.
NOT ONLY WERE PATIENTS FOUND TO
HAVE LOWER HEMOGLOBIN LEVEL AND
PATIENTS NOT TRANSFUSED BUT
THERE WAS SIGNIFICANT ELEVATIONS
IN ACTIVATION SHOWN WITH
COMPLIMENTS AND IT'S ONCE AGAIN
THE PATHWAY BLEED AND NOT ONLY
WERE BV LEVELS ELEVATE AND C5A
LEVELS AND OTHER LEVELS
ELEVATED.
THESE RESULTS SUGGESTED THE
ACTIVATION MAY OCCUR DURING A
SEVERE COMPLICATION SICKLE CELL
DISEASE SUCH AS ACUTE CHEST.
THEY'RE CORRELATIVE IN NATURE
AND WHETHER THE SYSTEM MAY BE
INVOLVED IN THE PROCESS.
SO TO DO THIS WE TURNED IN A
CHEST MODEL AND WHEN WE INJECTED
THE MICE TO MIMIC HEMOLYSIS THE
WILD TYPE A MICE THERE WAS NO
APPRECIABLE DIFFERENCE IN
CONTRAST THERE WAS AN INCREASE
IN C5 AND A COMPLIMENT MAY BE
ACTIVATING THE MICE AND MAY
CONTRIBUTE TO THE PANELO
PHYSIOLOGY OF ACUTE CHEST
SYNDROME.
AND NOT ONLY DO WE SEE IT
ELEVATED IN THE PLASMA BUT WE
LOOKED AT THE LUNG AND FOUND
COMPLEMENT WAS INCREASED IN
TERMS OF DEPOSITION OF
ENDOTHELIAL CELLS BUT NOT IN THE
WILD TYPE A MICE.
NOT ONLY COMBINANT POSITION AND
SAW CHANGES IN O2 STATS AND
CONSISTENT WITH CARDIOVASCULAR
COMPLICATIONS ASSOCIATED WITH
INJECTION ULTIMATELY RESULTED IN
INCREASED MORTALITY SPECIFICALLY
IN THE MICE WITH SICKLE CELL
DISEASE AND NOT WITH THE WILD
TYPE CONTROL.
THESE RESULTS SHOW ACUTE
CHEST-LIKE FEATURES IN THE MICE
ASSOCIATED WITH ACTIVATION.
IT DIDN'T DEMONSTRATE THE
COMPLEMENT INVOLVED IN THE
PROCESS AND THE COMPLEMENT CAN
DRIVE THE SAME PATHOPHYSIOLOGY
SPECIFICALLY SICKLE CELL DISEASE
MICE AND WE BYPASSED AND WE
INJECTED WHAT'S BEEN USED FOR
ALMOST HALF A CENTURY MORE TO
ACTIVATE COMPLEMENT AND DEPLETE
IT IN DOING SO WE FOUND UNLIKE
WILD TYPE MICE WHICH HAD AN
INCREASE IN ACTIVATION WERE MORE
PRONOUNCED.
NOT ONLY DO WE SEE INCREASED
LEVEL OF COMPLEMENT ACTIVATION
BUT THERE WAS A SIGNIFICANT
DECREASE IN THE HEMATOCRIT AND
SUGGESTING HEMOLYSIS INDUCED IN
THE MICE FOLLOWING EXPOSURE TIE
FACTOR THAT CAN ACTIVATE
COMPLIMENT.
WE LOOKED AT MORTALITY WE SAW
THE INJECTION SPECIFICALLY
RESULTED IN FATALITY IN THE
SICKLE CELL AND NOT WILD TYPE
CONTROL AND MOST MICE AREN'T
EXPOSED DELIBERATELY OR PATIENTS
TO THIS BUT WITH HEMOLYSIS MAY
DRIVE ACUTE CHEST THROUGH AN
ACTIVATION PATHWAY WE CROSSED
THE MICE WITH THE KNOCKOUT AND
TOOK OVER TWO AND A HALF YEARS
TO GENERATE THE MICE AND WE ASK
THE QUESTION IS COMPLIMENT
REQUIRED OR INVOLVED IN
HEMOLYSIS AN WE INJECTED MICE
AND WILD TYPE INJECTED WERE
RESISTANT AND AT LEAST IN THE
MODEL WE EXPOSED THE SAME MICE
TO THIS AND THEY WERE RESISTANT
TO COMPLEMENT ACTIVATION INDUCED
ACUTE CHEST.
AND IN THE MODEL THAT COMPLEMENT
MAY BE INVOLVED AND GIVEN THE
COMPLEMENT ACTIVATION
CORRELATIVE DATA IN ACUTE CHEST
AND WHAT WE SEE DURING THE
TRANSFUSION REACTION WHICH CAN
BE ACCOMPANIED BY HEMOLYSIS AND
MAY CONTRIBUTE TO SOME OF THE
PATHOPHYSIOLOGY THAT CAN OCCUR
DURING THE COMPLICATIONS.
DURING THE TIME WE CONDUCTED THE
STUDIES EARLY ON A FEMALE WITH
SICKLE CELL DISEASE PRESENTED
WITH A CLASSIC TRANSFUSION
REACTION AND YOU CAN SEE IT
OCCURRED AND HEMOGLOBIN
INCREASES AND THEN THE DECLINE
IN HEMOGLOBIN AND CONTINUES TO
FALL WITHIN THE THRESHOLD
CONSISTENT WITH HYPER HEHYPERHE
AND THE PATIENT GOT EPO AND WE
GOT RETUXI MMAB AND THEY TRIED
USE ECCOLUMAB AND LOOKED AT THE
ACTIVATION AS OUTLINED WITH BV
AND FOUND THE ACTIVATION WAS
SHUT DOWN AS THE HEMOGLOBIN
BEGAN TO INCREASE AND SO THEY
RECEIVED A SECOND DOSE WHICH
SHUT DOWN THE ACTIVATION AND
RESULTING IN THE ACTIVATION OF
THE REMOVAL AND THE PATIENTS WE
NOW TREATED WITH ECULIZUMAB AND
THEY WOULD NOT MAKE IT TYPICALLY
IN THE SITUATION WHICH COULD
HAVE BEEN TREATED WELL.
CLASSICALLY WE THINK OF INDUCING
MEMORY B CELLS FOR RESPONSE TO
DRIVE FORMATION TO ENGAGE AND
CAUSE HEMOLYSIS AND CAN ACTIVATE
AND CAUSE HEMOLYSIS OF THE
PATIENT'S OWN CELLS AND
POTENTIALLY CONTRIBUTE TO HYPER
HEMOLYSIS AND IT'S OCCURRING TO
CAUSE HEMOLYSIS INDEPENDENT OF
ANTIBODIES.
THIS HAS BEEN A STRIFE IN
PREVIOUS STUDIES WHERE 30% OF
THE DCRs WERE PRESENT WITHOUT
ANY DETECTABLE ANTIBODY BUT
REGARDLESS NO ANTIBODY IS
DETECTED BUT WHETHER IT'S TRULY
NOT USED WITH ASSAYS NEEDS TO BE
DETERMINED AND HEME CAN ACTIVATE
FURTHER COMPLEMENT PATHWAYS TO
DRIVE POSSIBLY HEMOLYSIS OF THE
PATIENT'S CELLS.
THIS HOPEFULLY ILLUSTRATES THE
CHALLENGES THAT CAN RESULT FROM
TRANSFUSION PATIENTS WHO ARE
ALLO IMMUNIZED AND WE LOOKED AT
THIS DIRECTLY BUT HEME AND
COMPLEMENT MAY PLAY SOME ROLE IN
THIS PROCESS.
OF COURSE ADDITIONAL STUDIES ARE
NEEDED TO DETERMINE IF THIS IS A
CASE WHETHER IT MAY BE
POTENTIALLY A PREVENTATIVE
MEASURE TO DO STUDIES IN THE
FUTURE.
WITH THAT I'D LIKE TO THANK ALL
THE PEOPLE IN THE LAB THAT DO
THESE STUDIES ONCE AGAIN AND I
WANT TO HIGHLIGHT SATISHA KNOT A
WONDERFUL COLLEAGUE AND FRIEND
WHO DROVE ALL THE STUDIES I
SHOWED IN THE MOUSE MODELS AND S
AND HAS HIS OWN LAB AT EMORY AND
DOING WELL AND ANOTHER STUDY OF
FACTORS THAT DRIVE
ALLOIMMUNIZATION AND HAPPY TO
ANSWER QUESTIONS IF I CAN JO
JOINON -- JOIN ONLINE DURING THE
SESSION.
>> WE'RE SORRY HE WASN'T ABLE TO
JOIN IN PERSON.
I THINK OUR NEXT SPEAKER IS
LIVE.
FOR THOSE WHO AREN'T AWARE, IF
YOU WANT TO SUBMIT A QUESTION
ONLINE JUST PRESS THE BUTTON
THAT SAYS SEND LIVE FEEDBACK.
IF YOU QUESTIONS IN PERSON YOU
CAN COME TO ONE OF THE
MICROPHONES.
DR. STELLA CHOU WILL TALK TO US
ON MOLECULAR GENOTYPING THE WAY
FORWARD FOR FINDING COMPATIBLE
ANTIBODIES.
SHE PRACTICES PEDIATRIC
HEMATOLOGY AND FOUND PATIENTS
WITH SICKLE CELL DISEASE CAN
CONTRIBUTE TO ALLOIMMUNIZATION.
>> WE'LL SWITCH GEARS AND TALK
ABOUT PREVENTION OF
ALLOIMMUNIZATION AND TALK WITH
PHENOTYPING TO HELP WITH SOME OF
THE DIFFICULT CASES.
I HAVE NO CONFLICTS OF INTEREST
TO DISCLOSE AND DISCUSS
ALLOIMMUNIZATION AND USING
ANTIGEN GENOTYPES AND DISCUSS
THE RED CELL TRANSFUSION.
MANY STILL RECEIVE THERAPY FOR
STROKE PREVENTION AND IT'S OFTEN
A PREREQUISITE FOR TRIALS.
ALLOIMMUNIZATION REMAINS A
CHALLENGING COMPLICATION AND CAN
PRECLUDE SOME OF THESE PATIENTS
FROM CURATIVE THERAPY DUE TO THE
INABILITY TO PROVIDE SAFE
TRANSFUSION SUPPORT.
SO AS MANY OF YOU ARE AWARE, THE
AMERICAN SOCIETY OF HEMATOLOGY
PUT OUT CLINICAL PRACTICE
GUIDELINES FOR SICKLE CELL
DISEASE AND ONE WAS FOR
TRANSFUSION SUPPORT.
IN THE GUIDELINES WE WERE ABLE
TO RECOMMEND ANTIGEN MATCHING
FOR RH AND CAL ANTIGENS FOR ALL
PATIENTS WITH SICKLE CELL
DISEASE AND THIS BECAME A STRONG
RECOMMENDATION BECAUSE WE WERE
ABLE IT LOOK BACK AT THE DATA
AND HAD MODERATE LEVEL OF
EVIDENCE.
WE ALSO RECOMMENDED THAT AN
EXTENDED PHENOTYPE FOR ALL
PATIENTS WITH SICKLE CELL
DISEASE BE ATTAINED AT THE
EARLIEST OPPORTUNITY AND IT WAS
A RECOMMENDATION BUT THAT THE
GENOTYPE WOULD BE PREFERRED OVER
A SEROLOGIC PHENOTYPE.
DESPITE MATCHING FOR ALMOST
THREE DECADES ANTIBODIES REMAIN
THE MOST COMMON SPECIFICITY WITH
PATIENTS WITH SICKLE CELL
DISEASE AND PATIENTS TRULY
AREN'T RH MATCHED WHEN PROVIDING
MATCHING DIVERSITY IN THE
PATIENTS WITH DONORS WITH
AFRICAN AMERICAN DESCENT HAVE
DIFFERENCES.
YOU CAN SEE APPROXIMATELY
TWO-THIRDS OF ANTIBODIES ARE
AGAINST THE RH SYSTEM.
AND WHAT'S INTRIGUING HERE IS
THAT IN THE BLUE ARE PATIENTS
WHO ARE ANTIGEN POSITIVE YET
MADE THAT ANTIBODY SPECIFICITY.
AND THOSE WE THINK ARE DUE TO
TWO THINGS.
30% OF THOSE ARE ANTIBODIES THAT
ARE ATTRIBUTED TO THE PATIENT'S
OWN TYPES.
THE TYPE IS D POSITIVE
SEROLOGICALLY BUT IT SHOWS A
PARTIAL DE-ANTIGEN AND BECOME AL
ALLOIMMUNIZED TO THE EPITOPE AND
THERE'S SOME EVIDENCE FROM CASE
REPORTS THAT RH VARIANTS IN THE
DONOR RED CELLS ARE AN UNDER
APPRECIATED RISK FACTOR FOR
ALLOIMMUNIZATION.
THERE'S RHD AND RHCD AND THEIR
VARIOUS COMBINATIONS AN THERE'S
TWO VARIANTS, A PARTIAL D
ANTIGEN THAT RESULTS FROM TWO
AMINO ACID CHANGES FROM THE
CONVENTIONAL D ANTIGEN AND I
SHOW AN EXAMPLE OF A COMMON
VARIANT THAT NOT ONLY CAUSES A
PATIENT WHO HAS THE ANTIGEN TO
EXPRESS PARTIAL C AND TO EXPRESS
AN ADDITIONAL ANTIGEN THE S
WHICH IS AN ANTIGEN INDIVIDUALS
WILL LACK AND IF YOU ARE EXPOSED
TO A DONOR THAT IS VS POSITIVE
BUT YOU YOURSELF ARE VS NEGATIVE
THAT PUTS YOU AT RISK AND WE SEE
PATIENTS RECEIVE BLOOD FROM
BLACK DONORS AND THEN DEVELOPING
THESE ANTIBODIES THAT WE CALL
ANTIBODIES TO LOW PREVALENCE
ANTIGENS.
AND THEN THE OTHER THING TO
POINT OUT HERE IS THE LOSS OF I
COMMON ANTIGEN HRP AND TALK
ABOUT THAT LATER WITH A
PARTICULAR CASE AND THE PATIENTS
WITH VARIANTS LACK WHAT WE CALL
A HIGH PREVALENCE ANTIGEN
MEANING MOST OF THE POPULATION
WILL EXPRESS THAT ANTIGEN AND
THE PATIENT MAKES AN ANTIBODY TO
THAT IT BECOMES DIFFICULT TO
FIND THE BLOOD THAT'S LACKING
AND THAT'S WHERE WE OFTEN TIMES
GET IN TROUBLE.
SCO RH VARIANT ARE QUITE
PREVALENT IN PATIENTS WITH
SICKLE CELL DISEASE AND THE
BLACK DONORS NEEDED TO SUPPORT
CEK MATCHING PROGRAMS.
SO HOW DO WE USE COMPREHENSIVE
PHENOTYPING?
WE GET A COMPREHENSIVE RH ALLELE
AUTHENTICATION FOR ALL PATIENTS
PERFORMED AT THE FIRST VISIT
WITH THE GENOTYPE PROVIDING
ANTIGEN INFORMATION ON 30 TO 35
ANTIGENS.
IT ALSO INFORMS ANTIBODY TEST TO
DIRECT OUR ANTIBODY
IDENTIFICATION AND USED TO GUIDE
PROPHYLACTIC RH MATCH
TRANSFUSIONS.
WHAT WE DO IS THERE'S A SUBSET
WE CONSIDER HIGH RISK RH
VARIANTS AND GIVE THE PATIENTS
ANTIGEN NEGATIVE RED CELLS
CONSISTENT WITH PROVIDING CEK
MATCH RED CELLS.
PATIENTS WHO HAVE ALLELES AND
CODING PARTIAL C WHICH I SHOW AN
EXAMPLE HERE, THIS ALLELE CAUSES
A PATIENT TO NOT EXPRESS D FROM
THE D LOCUS BUT EXPRESS A
PARTIAL BIG C AND THE PATIENTS
WILL TYPE STRONGLY BIG C
POSITIVE OR SEROLOGIC TEST
BUDGET IF EXPOSED TO
CONVENTIONAL BIG C BLOOD WILL
FORM ANTI-BIG C AND THEY'RE PUT
ON BIG C NEGATIVE BLOOD AND
THOSE ENCODING PARTIAL D ARE PUT
ON D NEGATIVE BLOOD
PROPHYLACTICALLY AND IF YOU'RE
UNABLE TO OB TAPE PHENOTYPING
FIRE PATIENT WE RECOMMEND THOSE
WHO ARE RN IMMUNIZED ARE
ALLOIMMUNIZED HAVE THE TESTING
BECAUSE IT DEPENDS ON THE
INSURANCE.
THE FIRST IS A 12-YEAR-OLD WITH
AUTOIMMUNE HEPATITIS AND NO
PLATELET COUNT WAS 87,000 AND
NEEDED A HEMOGLOBIN OF 4.2.
THEY ORDERED BLOOD BUT SHE'S
DIFFICULT TO MATCH BECAUSE SHE
MADE PREVIOUS ANTIBIG-C AND
LITTLE HRB AND CLEARLY SHE WAS A
PATIENT WHO SOME WOULD CALL A
RESPONDER WITH THREE LIFE TIME
TRANSFUSIONS AND THREE UNITS
EXPOSURE.
I SHOW HER EXTENDED PHENOTYPE
HERE AND HER RH PHENOTYPE SHOWS
SHE ESSENTIALLY HAS A PARTIAL D
ANTIGEN.
THIS ALLELE INCLUDES MORE OF A
SNIP LIKE THAT WE THINK OF FOR
RHD BUT SHE IS HOMOZYGOUS FOR
THIS ALLELE WHICH MEANS SHE HAS
PARTIAL LITTLE C AND LITTLE E
AND IS NEGATIVE FOR THE HRP
ANTIGENS SHE BECAME IMMUNIZED
TO.
TO FIND THESE ANTIGENS EIGHT
POTENTIAL DONORS IN THE RARE
DONOR PROGRAM WERE IDENTIFIED AS
BEING A MATCH BUT THERE WERE NO
DONOR UNITS AVAILABLE AT THE
TIME SO SHE WAS NOT TRANSFUSED
AND GIVEN SUPPORTIVE CARE.
HOWEVER, HER HEMOGLOBIN WAS AT 4
AND SPLENECTOMY NEEDED AND
NEEDED TRANSFUSION TO GO TO THE
O.R.
AGAIN THE HOSPITAL IDENTIFIED NO
COMPATIBLE UNITES BUT WE
CONTACTED AN ALTERNATIVE BLOOD
SUPPLIER WITH A FROZEN UNIT AND
SHE NEEDED A HOMOZYGOUS DONOR
AND THAT'S WHAT WAS LOCATED FOR
HER.
HER SURGERY WAS DELAYED BECAUSE
SHE MADE SO MANY ANTIBODIES WITH
ONLY THREE TRANSFUSIONS AND
TREATED HER WITH RITUXIMAB AND
MEASURED HER B CELL RESPONSE AND
SHE GOT A PRE-OP TRANSFUSION
WITH THE UNIT AND LOOKED AT DATA
FROM FOUR YEARS OF TRANSFUSION
OF 200 PATIENTS WE CARED FOR AND
LOOKED AT THE FREQUENCY OF RH
VARIANTS IN THE BLACK AND WHITE
DONOR POPULATIONS.
WE FOUND IT WAS FEASIBLE WITH A
ROBUST BLACK DONOR POOL.
OF THE 200 PATIENT THE PERCENT
MATCHED WITH THE PHENOTYPE AND
THE DONOR UNITS.
IF YOU GENOTYPE THIS MANY DONORS
PER DAY AND YOU CAN SEE WITH THE
BLACK DONORS WE WOULD BE ABLE TO
FIND THE GENOTYPE MATCHED UNITS
MORE READILY THAN WHITE DONORS
BECAUSE THEY WILL OFTEN TIME
HAVE THE SAME ALLELES AND WE'RE
REACHING HIGH 90% IF WE'RE
PHENOTYPING MORE THAN 90 DONORS
A DAY FOR THE POPULATION AND
COMPARED TO SEROLOGIC MATCHING
WE FOUND WE'D NEED TO SCREEN
TWICE AS MANY BLACK DONORS AS
SEROLOGIC SCREENING.
WE OPENED UP A STUDY FOR
PATIENTS WITH CHRONIC
TRANSFUSIONS IN A COLLABORATION
AT THE NEW YORK BLOOD CENTER AND
RESEARCH COORDINATOR AND THEY
SCREENED BLACK AND HISPANIC
DONORS AND THOSE THAT PASSED FOR
THE GENOTYPE WERE
COMPREHENSIVELY GENOTYPED.
THIS IS OUR APPROACH FOR RH
GENOTYPE MATCHING.
THIS IS AN EXAMPLE OF A
PATIENT'S GENOTYPE.
WE CAN PROVIDE AN EXACT RH MATCH
WITH ALL FOUR ALLELES AND USE
WHAT WE CALL LESS RESTRICTIVE
MATCH.
WE THINK OF THE CE48C AS
EQUIVALENT TO THE CONVENTIONAL
ALLELES.
SO THIS IS A PILOT STUDY.
THE GOAL WAS TO REACH 10
PATIENTS SIMULTANEOUSLY BEING ON
STUDY TO DATE.
WE'VE ENROLLED 15 PATIENTS WHO
HAVE BEEN ALL PEDIATRIC PATIENTS
AND THUS FAR 250 TRANSFUSION
UNITS FOR THE PATIENT REQUIRE
SIMPLE OR STRAIGHT TRANSFUSION A
TOTAL 267 GENOTYPE UNITS HAVE
BEEN TRANSFUSED TO THIS COHORT.
THIS PIE CHART SHOWS THE LEVEL
OF RH GENOTYPE MATCHING WE WERE
ABLE TO PROVIDE.
SO 100% GOT RH GENOTYPE MATCHED
OF THE 100%, 13% WERE THE LESS
RESTRICTIVE MATCH WHERE WE
ALLOWED THE INTERCHANGE WITH
CD48C WITH CE.
WE HAD A FEW OFF STUDY
TRANSFUSIONS FOR INSTANCE A
PRIORITY OF A PATIENT CAME IN
FOR AN ACUTE TRANSMISSION THEY
WOULD LIKELY NOT GET GENOTYPE
MATCHED UNITS.
I JUST WANT TO SHOW BECAUSE I
THOUGHT IT WAS INTERESTING DATA
WE KEPT TRACK OF OUR BLOOD
SUPPLIER OUR COLLABORATORS IN
THE NEW YORK BLOOD CENTER AND
THIS IS PRECOVID THEY WERE
COLLECTING NEARLY 6,000 UNITS
FROM BLACK DONORS PER QUARTER.
AND THIS IS WHERE COVID STARTED.
THIS IS ACTUALLY WHEN WE OPENED
OUR STUDY.
YOU CAN SEE THEY WERE HAVING A
VERY DIFFICULT TIME NOT FOR OUR
STUDY IN PARTICULAR BUT JUST NOW
SEVERAL YEARS LATER APPROACHING
THOSE BASELINE LEVELS OF BLACK
DONATIONS.
IN TERMS OF THE OUTCOMES TO DATE
AS EXPECTED WE HAVE SEEN NO RX
ALLOIMMUNIZATION AND HAVE NOT
SEEN THE RH MATCHED UNITS FOR
THEM AND YOU CAN SEE HERE OUR
INSTITUTIONAL POLICY IS TO
PROVIDE UNITS THAT ARE LESS THAN
21 DAYS OLD FROM COLLECTION AND
IN EACH BAR FROM THE PATIENT IS
PRE STUDY AND ON STUDIO AND YOU
CAN SEE MOST HAVE RECEIVED ALL
UNITS LESS THAN 21 DAYS.
ONE STARRED AND THE ONE WE
SCHEDULED THE MOST.
AND THEN SHOWN HERE BELOW IS THE
HEMOGLOBIN S AND NO STATISTICAL
DIFFERENCE BUT THERE'S A TREND
FOR SOME PATIENTS OF IMPROVED
CONTROL OF THEIR HEMOGLOBIN S
MATCHED BLOOD.
WE THINK IT'S LIKELY FEASIBLE
AND CAN MINIMIZE
ALLOIMMUNIZATION AND REQUIRE A
ROBUST POOL AND CERTAINLY THERE
ARE ISSUES WITH EFFICIENCY ONCE
THERE'S MORE SCALE UP AND WE
THINK THIS CAN ALLOW PRECISE RED
CELL ANTIGEN MATCHING AND THE
RATE IS ONE ANTIBODY PER 250
UNITS TRANSFUSED AND WHILE WE'VE
NOT IDENTIFIED ANY RH ANTIBODIES
IF WE GET TO 4,000 UNITS WE'D
HAVE A SIGNIFICANT P VALUE IF
THERE WAS EVEN LESS THAN 5RH
ANTIBODIES MADE.
SO THE SECOND CASE IS THE
5-YEAR-OLD BOY WE TOOK CARE OF
NOW ALMOST 10 YEARS AGO WHO HAS
HEMOGLOBIN SS WHO PRESENTED TO
THE EMERGENCY ROOM AND THIS IS
HIS URINE ON PRESENTATION.
HE HAD BEEN TRANSFUSED ONE UNIT
OF O POS 10 DAYS PRIOR FOR A
HEMOGLOBIN OF 6.5 AND IT WAS 4.2
WITHIN 24 HOURS AND HEMOGLOBINI
WAS 7 AND 4.2 THE NEXT DAY AND
THE ANTIBODY EVALUATION FIRST
FOOLED OUR BLOOD BANK TECHNOLOGY
AND IT TURNED OUT THE ONE CELL
WAS A D NEGATIVE CELL BUT
BECAUSE HE WAS D POSITIVE THEY
DIDN'T THINK HE'D HAVE AN ANTI-D
BUT THAT'S WHAT HE HAD AND WHEN
WE PHENOTYPED WE SAW HE WAS HEMO
ZYGOUS FOR THE PARTIAL D ANTIGEN
AND HAD BECOME DE-IMMUNIZED
BECAUSE HE'S A PATIENT WITH
PARTIAL D.
ANTI-D DOES OCCUR AN IN PATIENTS
WITH PARTIAL D ANTIGENS AND CAN
ALSO OCCUR IN PATIENTS WITH
CONVENTIONAL RHD TRANSFUSED WITH
UNITS PRIMARILY FROM BLACK
DONORS.
AND WHAT BECOMES CHALLENGING IS
ONCE WE HONOR THE ANTI-D.
WE DON'T EXPOSE THEM TO D
POSITIVE BLOOD AND PROVIDING
D-NEGATIVE RED CELLS TO PATIENT
WITH ANTI-D HAS A SIGNIFICANT
IMPACT ON THE D-NEGATIVE RED
CELL INVENTORY.
SO ONE QUESTION WE HAD WAS WERE
ALL THE PATIENTS SIGNIFICANT AND
CAN THEY WESTBOUND EXPOSED TO D
POSITIVE BLOOD?
WE LOOKED RETROSPECTIVELY AT OUR
DATA.
WE CATEGORIZED D POSITIVE INTO
THREE CATEGORIES.
DECONVENTIONAL ONE CONVENTIONAL
ALLELE FROM A PARTIAL D AND THIS
WAS 7% OF THE PATIENTS.
38% OF WHOM WHO WERE ON CHRONIC
TRANSFUSION AND D-POSITIVE DOW
ZERO WE THINK OF AS SIMILAR TO
RHD CONVENTIONAL AND NO
CONVENTIONAL ALLELE AND THIS IS
13% OF THE PATIENTS OF WHICH 44%
OF THE CHRONIC TRANSFUSED WERE
IN THE COHORT AND LASTLY THE D
POSITIVE PARTIAL WHERE THEY
COULD BE HEMEZYGOUS OR COMPOUND
HETEROZYGOUS.
AND THOSE WERE THE LAST SET OF
PATIENTS.
IF WE LOOKED AT ALL THE ANTI-D
FORMED THERE WAS 48 ANTI-D
ALTOGETHER AND YOU CAN SEE HERE
IS THE PERCENTAGE OF THE
PATIENTS WHO HAD FORMED ANTI-D
AND THE PARTIAL D COHORT 20% HAD
FORMED ANTI-D WHERE IT WAS CLOSE
TO 5% FOR THE CONVENTIONAL IN
THE DOW ZERO.
IF YOU LOOK AT ANTI-D RATE YOU
CAN SEE IT WAS THREE TO FIVE
TIMES HIGHER FOR THE PATIENTS
WITH PARTIAL D COMPARED TO
CONVENTIONAL D GROUPS.
AMONG THESE 48 INDIVIDUALS, 13
HAD A DELETE TRANSFUSION
REACTION OR POORER TRANSFUSED
RED CELL SURVIVAL BY LOOKING AT
THEIR HEMOGLOBIN S THE PATIENTS
WHO MADE ANTI-D BECAUSE THEY
WERE EXPOSED TO DONOR BLOOD WITH
A VARIANT SOMETIMES ALSO HAD A
CLINICALLY SIGNIFICANT REACTION
TO THAT BLOOD.
WE LOOKED AT THE OTHER ASPECTS
OF THE ANTI-D AND THE PATIENTS
WHO HAD PARTIAL D TEND TO MAKE
THEIR ANTI-D AT LOWER D POSITIVE
UNIT EXPOSURES.
MANY PATIENTS ARE CHRONICALLY
TRANSFUSED AND THE PATIENTS WITH
PARTIAL D FREQUENTLY MADE THE
ANTIBODY EARLY ON IN THEIR
EXPOSURES AND IF WE LOOKED AT
HOW LONG WE COULD SEE THE ANTI-D
PERSIST IN THEIR PLASMA THEY'RE
CHRONICALLY TRANSFUSED THE
ANTI-D PERSISTED LONGER IN THE
PATIENT PLASMA COMPARED TO THE
DOW O.
THE RATE OF ANTI-D WAS HIGHER
WITH PATIENT WITH PARTIAL D AND
MADE IT WITH LOWER EXPOSURES AND
THE ANTI-D PERSISTED IN THE
PLASMA LONGER.
AND SO PATIENTS WITH POTENTIAL D
CAN BENEFIT FROM TRANSFUSION AND
THAT'S WHAT WE DO FOR OUR
PATIENT AT OUR INSTITUTION.
IT HAS A SIGNIFICANT INCREASE OF
IMPACT FOR THOSE WHO REQUIRE D
NEGATIVE BLOOD.
AMONG THE COHORT OF 48, 32
PATIENTS WERE ON CHRONIC
TRANSFUSION AND REQUIRING AN
AVERAGE OF 62D NEGATIVE UNITS
PER YEAR PER INDIVIDUAL AND CAN
PATIENTS RECEIVE D POSITIVE RED
CELLS?
WE HAVE A FEASIBILITY STUDY IN
PROVIDING RDH MATCHED BLOOD ON
CHRONIC BLOOD CELL EXCHANGE TO
BE ELIGIBLE THE ANTI-D CANNOT BE
IN THE PAST SIX MONTHS AND THE
PATIENTS ARE ALL ON CHRONIC RED
CELL EXCHANGE WITH THE IDEA
RE-EXPOSE A PATIENT WITH FIVE
UNITS WITH ONE D POSITIVE UNIT
BECAUSE IT WOULD NOT BE
LIFE-THREATENING AND WE HAVE
THEM SUBSEQUENTLY COME BACK FOR
LABS A WEEK AFTER THE
TRANSFUSION TO MAKE SURE THE
ANTI-D HAS NOT REAPPEARED AND
THEN PROGRESSIVELY INCREASED THE
NUMBER OF D POSITIVE UNITS THEY
GET.
WE HAVE FOUR PATIENTS WHO HAVE
COMPLETED THIS.
EACH OF THE PATIENTS FOR THE
FIRST TWO VISITS GETS ONE D
POSITIVE AND THEY'RE ALL
PATIENTS THAT HAVE AT LEAST ONE
CONVENTIONAL RHD ALLELE AND YOU
CAN SEE OFTEN TIMES THE PATIENTS
ARE IMMUNIZED MAKING IT HARDER
TO FIND THEIR BLOOD AND FOR ALL
THESE PATIENTS EXCEPT THE LAST
ONE GOT BLOOD WITH TWO
CONVENTIONAL RHD ALLELE AND ONE
PATIENT GOT ONE WITH DOW 0.
IT DID NOT REAPPEAR AND THERE
WAS NO DIFFERENCE IN THEIR
HEMOGLOBIN S YOU CAN SEE PRESTUT
STUDY ON THE LEFT AND NO
DIFFERENCE IN THE AGE OF THEIR
UNITS AT THE TIME OF
TRANSFUSION.
TO CLOSE OUT A COMPREHENSIVE
PHENOTYPING CAN GUIDE DONOR
CHOICE AND SELECT BLOOD CELLS
FOR LESS CHALLENGING CASES AND
RHD MATCHED RED CELLS IF THE
FUTURE WOULD REQUIRE A ROBUST
AFRICAN AMERICAN DONOR POOL AND
MORE COST-EFFECTIVE NGS ASSAYS
WHICH I THINK WILL BE COMING IN
THE NEXT FEW YEARS BEING REALLY
A PARADIGM FOR USING MOLECULAR
TYPING FOR ALL PATIENTS.
I WANT TO END BY THANKING OUR
TWO RESEARCH COORDINATORS AND
OUR BLOOD BANK AND NURSING AND
THE NEW YORK BLOOD CENTER.
THANK YOU.
>> THANK YOU FOR THE EXCELLENT
TALK.
DOES ANYBODY HAVE ANY QUESTIONS?
THERE ARE NONE IN THE CHAT.
>> THAT WAS WONDERFUL.
THANK YOU SO MUCH.
I HAVE A COUPLE QUESTIONS.
FIRST IS THE PARTIAL D HAVE THE
ANTIBODY LONGER?
>> IT'S A COMPLETE LACK OF
ANTIGEN AND THE FOLKS WITH
CONVENTIONAL D ARE SEEING A D
ANTIGEN THAT'S SLIGHTLY
DIFFERENT AND WE'RE NOT ALWAYS
IT'S A D ANTIGEN.
IT COULD BE THE CE ANTIGEN
DIFFERENT.
>> THE SECOND QUESTION YOU'RE
LOOKING TO DEVELOP A CHIP TO DO
DIRECT GENOTYPES OR A BROAD NEXT
GEN EVOLUTION SEQUENCING?
>> THINK SOME ARE LOOKING AT
CHIPS.
IT'S COMPLEX AND BECAUSE THE
VARIATION COMES FROM PIECES OF D
GOING TO CD YOU CAN'T USE
STANDARD NGS STANDARD.
WE'RE WORKING AT THE NEW YORK
BLOOD CENTER ON TRYING TO
DEVELOP A BIO INFORMATIC PATHWAY
FOR NGS-BASED PATHWAYS USING
MORE OF THE QPCR BASED TO LOOK
AT COPY NUMBER RATHER THAN
RELYING ON A COMPANY TO DEVELOP
CHIPS THAT ARE EXPENSIVE.
>> ARE THE MOLECULAR PHENOTYPING
ACCEPTED BY MOST BLOOD BANKS IN
THE UNITED STATES.
AND ADULTS OFTEN GET TRANSFUSED
AT PERIPHERAL SMALL COMMUNITY
HOSPITALS.
I'VE BEEN DOING SICKLE CELL FOR
A LONG TIME AND I DON'T SEE THIS
IMPROVING.
AND THE PERIPHERAL HOSPITALS AND
WHAT DO YOU SUGGEST WE CAN DO
THIS TO MAKE THIS MORE UNIFORM?
I REMEMBER PEOPLE DIDN'T WANT TO
DO DE BECAUSE IT WAS TOO
EXPENSIVE.
IT'S A PRACTICAL QUESTION.
>> IT'S A VERY GOOD QUESTION.
THERE'S A FEW COMMENTS I'LL
MAKE.
ONE IS I'M A HUGE ADVOCATE FOR
MOLECULAR TYPING BECAUSE WE'VE
SHOWN LESS ERROR BECAUSE IT'S
AUTOMATED VERSUS A TECHNOLOGIST
TYPING AND WRITING ON A PIECE OF
PAPER THAT THEN GETS TRANSCRIBED
IN A COMPUTER SYSTEM.
AND THE ONE-TIME TEST IS LESS
THAN ONE TRANSFUSION THAT'S
ADMINISTERED.
ACTUALLY A FRACTION OF THE
TRANSFUSION ADMINISTERED.
FOR A PATIENT LIFE TIME I THINK
WE CAN ALL JUSTIFY THAT COST.
WE DID A COST ANALYSIS OURSELVES
AND IN TERMS OF OUR BLOOD BANK
HAVING TO KEEP TECHNOLOGISTS
TRAINED ON THE SEROLOGIC TYPING
IT'S MORE COST EFFECTIVE TO DO
IT THROUGH OUR REFERRAL CENTER.
SO GENOTYPING IS REALLY DONE AT
REFERRAL CENTERS RIGHT NOW AND I
THINK YOU PROBABLY HAVE TO HAVE
MORE STANDARDIZED FORMATS
BECAUSE IF YOU SEND YOUR
GENOTYPING YOU'RE SAMPLE IN FOR
GENOTYPING AT ONE LABORATORY IT
CAN BE DIFFERENT FROM ANOTHER
LABORATORY.
I THINK THAT'S IMPORTANT.
LASTLY THE DEPARTMENT OF HEALTH
AND HUMAN SERVICES THERE'S A
COMMITTEE NOW THAT'S BEEN
ESTABLISHED TO MOVE FORWARD WITH
A NATIONAL REGISTRY FOR
ALLOANTIBODIES AND I ADVOCATE
FOR INCLUDING PHENOTYPES OR
GENOTYPES BECAUSE EXACTLY WHAT
YOU SAID, A PATIENT MAY GO TO
ANOTHER INSTITUTION EITHER
TRANSITION THERE OR BE
TRAVELLING OR CHOOSING TO GO TO
ANOTHER INSTITUTION AND WE
SHOULD BE ABLE TO SHARE THIS
INFORMATION READILY.
I THINK WE'RE LOOKING AT WAYS
FOR THE HOSPITAL LABORATORY
SYSTEMS TO DATA DUMP TO THE
CENTRAL COORDINATING CENTER
WHICH THEN WOULD BE AVAILABLE TO
ALL HOSPITALS INCLUDING
COMMUNITY HOSPITALS.
AT A MINIMUM I THINK IT WILL
MEAN IF YOU'RE THE INSTITUTION
PROVIDING THE TRANSFUSION YOU
CAN SEE WHERE A PATIENT HAS HAD
A HISTORY OR RECORD AND YOU CAN
CALL THAT INSTITUTION'S BLOOD
BANK AND MAKE SURE THE PATIENT
DOESN'T HAVE AN ANTIBODY NOT
CURRENTLY DEMONSTRATING AS WAS
SHOWN.
THANK YOU.
>> THANK YOU.
IS THIS AUDIO BETTER?
ALL RIGHT.
IT'S MY PLEASURE TO INTRODUCE
OUR THIRD SPEAKER IN THIS
SESSION, DR. NEIL HANCHARD WHO
RVSED HIS MEDICAL DEGREE FROM
THE UNIVERSITY OF KINGSTON
JAMAICA AND WAS A RHODE SCHOLAR.
HE COMPLETED HIS CLINICAL
TRAINING AS A PEDIATRIC TRAINING
AND HE'S A SENIOR INVESTIGATOR
IN THE CENTER FOR PRECISION
HEALTH WITHIN THE NATIONAL HUMAN
RESEARCH INSTITUTE WHERE HE
HEADS THE CHILDHOOD COMPLEX
DISEASE GENOMICS STUDIO.
DR. HANCHARD.
>> I LIKE TO CALL MYSELF A HUMAN
GENETICISTS.
I APOLOGIZE FOR THE SWITCH FROM
MAC TO WINDOWS AND UNDERSTAND
WHY THERE'S VARIATION IN DISEASE
RISK.
WE ASK SPECIFIC QUESTIONS AS WE
GO ALONG AND I'LL TALK ABOUT
WORK WITH THE QUESTION OF SOME
INDIVIDUALS MAKE ANTIBODIES AND
SOME DON'T AND WHAT UNDER LIES
ALL THE RESEARCH IS THE IDEA
MOST OF THESE DISORDERS ARE MUCH
MORE PREVALENT IN INDIVIDUALS OF
AFRICAN ANCESTRY.
AND WE THINK ABOUT THE
APPROACHES AND MODELS IN THESE
AREAS.
THIS IS PARTICULARLY IMPORTANT
BECAUSE INDIVIDUALS OF AFRICAN
AMERICAN ANCESTRY ARE UNDER
REPRESENTED IN GENETIC STUDIES
AND LOOKING AT GENOME WIDE
ASSOCIATION STUDIES WHERE
THERE'S TENS OF THOUSANDS AND
INDIVIDUALS OF AFRICAN AMERICAN
ANCESTRY COUNT FOR LESS THAN 1%
OF THE PARTICIPANTS HEALTH AND
YOU LOOK AT LARGE SEQUENCING
DATABASES STANDING AS THE
REFERENCE AND THE EUROPEAN BIO
BANK MUCH LESS AFRICAN AMERICAN
ANCESTRY AND AT ODDS OF WHAT WE
KNOW ABOUT AFRICAN ANCESTRY IN
GENERAL AND THE NUMBER OF
VARIANTS IN THE GENE VARY MORE.
THE BIG PICTURE VIEW IS THAT
THERE ARE FEWER STUDIES THAT
INVOLVED INDIVIDUALS WITH
AFRICAN ANCESTRY AND THERE'S
MORE VARIATION AND MORE
COMPLEXITY TO THAT VARIATION
WHICH ALSO COMES TO BEAR.
SO WE KNOW THIS FROM MANY OF THE
BLOOD ANTIGENS THEY'RE DIFFERENT
AS YOU LOOK AT DIFFERENT
ANCESTRAL GROUPS.
HERE AGAIN LOOKING AT THE BLOOD
GROUPS YOU CAN SEE FOR INSTANCE
IT'S EXTREMELY COMMON AMONG
INDIVIDUALS WITH AFRICAN
ANCESTRY AND WHAT WE DON'T KNOW
REALLY THE EXTENT OF THE
VARIATION ACROSS ALL THE BLOOD
GROUPS.
AND BY EXTENT HOW DOES THAT
RELATE TO THE SUBSEQUENT ANTIGEN
FORMATION AND THEN WHETHER OR
NOT WE COULD PERHAPS USE THAT
KIND OF INFORMATION TO INFORM
FOR A GIVEN POPULATION WHICH
ANTIGENS WILL BE OF PARTICULAR
IMPORTANCE TO THE PATIENT.
WE LOOKED AT GENETIC VARIATION
IN A POPULATION FROM BRAZIL.
SO THE SICKLE ALLELE 1 IN 400
VARIES ACROSS THE COUNTRY.
BUT THE ALLOUME IMMUNIZATION
RATE IS STILL HIGH AND WE LOOKED
AT HALF FROM SICKLE CELL
PATIENTS AND THE OTHER HALF NOT
AND WE'RE ABLE TO DO WHOLE
GENOME SEQUENCING FOCUSSING ON
THE 18 GROUPS YOU SEE
REPRESENTED IN THE TABLE HERE.
THIS IS ALL WORK DONE BY A
POSTDOC IN THE LAB.
THEY HAD BETWEEN 20 AND 30
VARIANTS.
SO PEOPLE ARE CARING A LOT OF
VARIANTS OVER THE 18 GENES THAT
ARE THERE.
ILLUSTRATED PREVIOUSLY.
WHEN YOU LOOK AT WHERE THE
VARIANTS ARE OCCURRING, WE CAN
SEE PERHAPS AS MAY BE EXPECTED
THE VAST MAJORITY OF THE
VARIANTS ARE OCCURRING IN THE
COMPLEMENT RECEPTOR 1 GENE.
MANY ARE HAVING AN EFFECT ON
PROTEIN BUT DON'T KNOW IF THE
AFFECT IS STRONG OR NOT BUT SEE
A NUMBER OF VARIANTS MUCH MORE
DELETERIOUS TO THE PROTEIN.
YOU CAN SEE THOSE REPRESENTED IN
DIFFERENT COLORS INCLUDING SOME
THAT ARE NOVEL HAVEN'T BEEN
RECORDED PREVIOUSLY AND IN MORE
THAN ONE OF THE GROUPS WE HAVE.
THERE'S A SUBSTANTIVE AMOUNT OF
VARIATION THAT OCCURS IN THE
GENES IN THE INDIVIDUALS AND WE
TRY TO RELATE THAT BACK TO THE
ANTIGEN ABOUT A THIRD ARE
WELL-KNOWN SORT OF VARIANTS THAT
INTERACT.
THERE'S A GROUP WHERE WE SEE A
VARIANT AND CHANGE AND DON'T
KNOW THE PARTICULAR IMPACT OF
THAT AND THERE'S A SUB GROUP
WHERE WE'VE NEVER SEEN THAT
VARIANT BEFORE AND DON'T KNOW
WHAT IT MEANS MOVING FORWARD.
THE BIG PICTURE TAKE HOME IS
THERE'S A LOT OF VARIATION WE'RE
TRYING TO CHARACTERIZE AND
UNDERSTAND.
THE BRAZILIAN POPULATION HAVE
EUROPEAN AND NATIVE AMERICAN
ASSENCESTRY AND THAT VARIES ACR
THE COUNTRY WHERE YOU FIND
PROPORTIONS.
THIS IS WHAT IT LOOKS LIKE ON A
POPULATION LEVEL.
WE CAN USE GENETICS TO
UNDERSTAND WHAT IT LOOKS LIKE ON
AN INDIVIDUAL LEVEL.
THIS IS A LINE GRAPH AND EACH
SAY DIFFERENT INDIVIDUAL.
EACH COLOR REPRESENTS THE
ANCESTRY.
THE GREEN IS AFRICAN AND THE
EUROPEAN IN BLUE.
INDIVIDUALS BOTH WITH SICKLE
CELL AND WHO DON'T HAVE SICKLE
CELL HAVE A COMBINATION IN
VARYING AMOUNTS OF THE PARTIALLY
AFRICAN ANCESTRY AND THERE'S
SLIGHTLY MORE GREEN HERE THAN
THE NON-SICKLE CELL INDIVIDUALS.
SO WHAT WE'RE INTERESTED IN IS
HOW DOES THIS ANCESTRY RELATE TO
THE GENETIC GENES THAT WE ARE
INTERESTED IN IN THE GENETIC
VARIATION UNDER LIES THAT.
IN TRUTH WHAT WE WANT IS MORE OF
THIS KIND OF APPROACH WHICH IS
SOMETHING WE CAN DO NOW TO PAINT
THE GENOME SO EACH CHROMOSOME
YOU CAN UNDERSTAND WHETHER
YOU'RE PROMINENTLY GOING TO BE
EUROPEAN AT THE SITE OR MOSTLY
AFRICAN AT THE SITE.
YOU CAN TELL INDIVIDUALS WHO
HAVE SICKLE CELL TEND TO HAVE
AFRICAN ANCESTRY OVER THE BETA
GLOBIN GENE AND THOSE WHO DON'T
DO NOT.
WE CAN TRY TO USE THAT
INFORMATION TO UNDERSTAND
WHETHER ANCESTRY INFLUENCES YOUR
RISK.
WE LOOK AT THE VARIOUS 18 GENES
YOU CAN SEE ON AVERAGE MOST OF
THEM HAVE AROUND 30% AFRICAN
ANCESTRY OVER THAT PARTICULAR
REGION OF THE GENOME.
AND YOU CAN SEE AS ALL OF YOU
KNOW THE ALLELE IS PARTICULARLY
COMMON AMONG INDIVIDUALS WITH
AFRICAN ANCESTRY AND HAVING AN
INCREASED ANCESTRY AT THIS LOCUS
MAY BE OF IMPORTANCE.
WHEN WE LOCK AT THE ANCESTRY IN
NON-SICKLE CELL INDIVIDUALS THEY
HAVE A HIGHER PROPORTION OF
AFRICAN ANCESTRY AND PERHAPS AS
A RESULT WE CAN SEE FOR INSTANCE
THEY HAVE A VARIANT EXPECTED TO
HAVE AN IMPACT UPON THE GENE BUT
THE VARIANCE IS SLIGHTLY HIGHER
WITH INDIVIDUALS WITH SICKLE
CELL DISEASE CONTRIBUTE TO THE
INCREASED RISK PARTLY BECAUSE SO
MANY RED CELL ANTIGENS ARE
IMPORTANT AND SECTORS ARE
IMPORTANT IN MALARIA AND MALARIA
PROTECTION.
WE ALSO KNOW THE RISK IS NOT
EVEN.
SO EVEN WITHIN INDIVIDUALS WITH
SICKLE CELL DISEASE THERE'S A
VARIATION IN TERMS OF
INDIVIDUALS WHO MIGHT DEVELOP
ANTIBODIES AND MIGHT NOT.
THIS IS NOT PURELY A FUNCTION OF
JUST WHETHER OR NOT HAVE YOU A
MISMATCH BUT IN FACT THE VAST
MAJORITY OF INDIVIDUALS
GENERALLY DON'T MAKE ANTIBODIES
BUT THERE'S A SUBSET OF
INDIVIDUALS WHO SEEM TO MAKE
ANTIBODIES ALMOST EVERY TIME
THEY GET A TRANSFUSION LEADING
TO THIS ALLOIMMUNIZATION
RESPONDER.
AND THE RESPONDER PHENOMENON IN
TURN IS A COMPLEX TRAIT.
THERE'S A NUMBER OF FACTORS THAT
CONTRIBUTE TO THIS.
THINGS LIKE AGE OF THE UNITS,
NUMBER OF TRANSFUSIONS ONE HAS
RECEIVED, THERE'S A GREAT DEAL
OF INTEREST IN THE IMMUNE
PRIMING OF SICKLE CELL DISEASE
AND HIGHLY INFLAMMATORY STATES
MAY CONTRIBUTE TO THIS AS WELL.
AND SO WE WANTED TO TAKE AN
APPROACH THAT WOULD ASK THE
QUESTION THAT'S OFTEN ASK OF
COMPLEX TRAITS WHICH IS THERE
SOMETHING ABOUT RECIPIENTS
GENOME OTHERWISE THAT MAY
INCREASE IN RESPONDING.
WE HAD ACCESS TO INDIVIDUALS WHO
HAD BEEN TRANSFUSED THROUGH THE
BLOOD BANKING IN SHREVEPORT,
LOUISIANA AND SERVE OKLAHOMA,
ARKANSAS, LOUISIANA AND
SOUTHEAST TEXAS.
AND THEY HAD INDIVIDUALS ABOUT
300 INDIVIDUALS ROUGHLY SPLIT
BETWEEN RESPONDERS AND
NON-RESPONDERS AND YOU CAN SEE
THE DEMOGRAPHICS OF THE CARE.
AND WE WERE ABLE TO GENOTYPE THE
INDIVIDUALS IN A STANDARD
GENOTYPING CHIP AND LOOK FOR
EVIDENCE OF ASSOCIATION.
YOU SEE IN THE PLOT THE HIGHER
THE DOT THE MORE SIGNIFICANT AND
YOU CAN SEE THESE TWO LOCI
CHROMOSOME 2 AND 5 WE FIND
ALMOST GENOME WIDE SIGNIFICANCE
AT THE PARTICULAR SNIP AND GIVEN
THE SAMPLE SIZE AND THE FACT
THAT WE'RE IN AFRICAN ASSENCEST
MAY NOT HAVE CAPTURED EVERYTHING
AND WE DECIDED TO SEE IF WE CAN
REPLICATE OUR ASSOCIATION.
WE HAD ACCESS TO ANOTHER COHORT
OF INDIVIDUALS FROM CHICAGO WHO
ALSO WERE DIVIDED INTO
RESPONDERS AND NON RESPONDERS
USING THE SAME CLINICAL CRITERIA
OF HAVING CLINICALLY SIGNIFICANT
ANTIBODIES AFTER MULTIPLE
TRANSFUSIONS AND YOU CAN SEE THE
DIFFERENCES AND THE REPLICATION
COHORT IS MUCH SMALLER THAN OUR
DISCOVERY SET.
WHEN WE LOOKED AT THIS WE FOUND
A SIMILAR ASSOCIATION WHICH IS
THE FREQUENCY OF THE VARIANT IN
OUR CASES IS MUCH HIGHER THAN IN
THE CONTROLS IN DISCOVERY AND
REPLICATION SET AND THAT'S
HIGHLY SIGNIFICANT WHEN YOU PUT
THE TWO OF THEM TOGETHER WITH
IMPARTING A FAIRLY ROBUST ODDS
OF BECOMING AN ALLOIMMUNIZATION
RESPONDER.
SECONDARILY, WE ALSO HAD THE
OPPORTUNITY TO LOOK AT
INDIVIDUALS WHO MADE MULTIPLE
ANTIBODIES MORE THAN THREE ALLO
ANTIBODIES LOOKING AT BEYOND
THAT AND WE CAN SEE WE FIND MOST
OF THE SIGNAL IS DRIVEN AND THE
COHORT HAS BEEN DRIVEN BY THE
ANTIBODY FORMERS.
AGAIN THE SAME FREQUENCY
DIFFERENCES AND STATISTICAL
SIGNIFICANCE.
SO INTERESTINGLY WHEN WE LOOK AT
THIS ON CHROMOSOME 5 YOU CAN SEE
THE FREQUENCY IN CASES AND
CONTROLS WHEN WE LOOK GLOBALLY
AND AVERAGE THE BIG DATABASES
IT'S ABOUT 2% WHICH IS KIND OF
WHAT YOU HAVE IN THE CONTROLS.
IF HOWEVER, YOU BREAK THAT DOWN
AND LOOK AT FREQUENCY IN THE
DATABASES AMONG WEST AFRICAN
INDIVIDUALS IT'S ALMOST 10% AND
COMPLETELY ABSENT FROM
INDIVIDUALS OF EUROPEAN
ANCESTRY.
SO IT WON'T BE A SURPRISE THAT
AT THIS POINT WE START TO THINK
ABOUT CAN WE INTRODUCE OUR SAME
SET OF MODELS OF THINKING ABOUT
ADD MIXTURE WHICH OCCURS IN THE
INDIVIDUALS WITH SICKLE CELL
DISEASE AND TRY TO UNDERSTAND
THE CONTRIBUTION OF THE VARIANT
TO DISEASE.
AND SO ON AVERAGE MOST OF
AFRICAN AMERICANS HAVE 20% TO
25% EUROPEAN ANCESTRY IN THE
COHORT IT'S SLIGHTLY LOWER
CONSISTENT WITH THE IDEA WE'RE
GENERALLY MORE AFRICAN ANCESTRY
IN THE INDIVIDUAL AND SEE WHAT
THAT LOOKS LIKE IN CHROMOSOME 11
OUR BENCH MARCH.
WE CAN SEE AT THE BETA GLOBIN
LOCUS BOTH CASES AND CONTROLS
THEY'RE ALMOST 100% AFRICAN
ANCESTRY AND SEE THE GENOME WIDE
AVERAGE.
WHEN WE LOOK AT CHROMOSOME 5 WE
CAN SEE THERE'S NOT A SYSTEMATIC
DIFFERENCE BETWEEN THE CASES AND
CONTROLS.
WHICH IS ACTUALLY GOOD BECAUSE
WHAT WE CAN DO THEN IS ADJUST
OUR ASSOCIATION BASED ON THE
PARTICULAR SNIPBACK GROUND THAT
WE HAVE.
AND WHEN WE DO THAT AGAIN YOU
CAN SEE AFRICAN ANCESTRY IS
CARRYING THE ASSOCIATION WHEREAS
INDIVIDUALS AND CONDITION ON
EUROPEAN ANCESTRY DON'T SEE THE
SIGNAL AND IT'S THE ONLY SIGNAL
WE CAN SEE ACROSS THE GENOME.
SO FAR WE'VE LOOKED AT MULTIPLE
POPULATIONS AND DATABASES AND
AGAIN THIS VARIANT VARIES
BETWEEN 5% AND 10% OF AFRICAN
ANCESTRY AND HAVEN'T SEEN IT
OUTSIDE THE GROUPS.
THE RECIPIENT GENETICS CAN BE A
CONTRIBUTOR TO WHY SOME
INDIVIDUALS ARE ALLOIMMUNIZATION
RESPONDERS WITH SICKLE CELL
DISEASE.
SO WE ARE TRYING TO TAKE THAT
FORWARD BY THINKING MORE WITH
THE INDIVIDUAL LOCUS AND THE
GENE THAT WE FIND THERE.
SO THIS PARTICULAR SNIP OCCURS
OVER AN ENHANCER AND BIND TO THE
REGULATORY ELEMENTS AND IT
OCCURS RIGHT IN THE LONG
NON-CODING GENE.
THIS IS THE LINK GENE NOT NOT A
LOT IS KNOWN ABOUT THE GENE
EXCEPT FOR THE IDEA IT'S
EXPRESSED IN BOTH THE LIVER AND
THE SPLEEN.
WHICH AGAIN ARE SITES OF
HEMATOPOYS -- HEMATOPOIESIS
BREAKDOWN AND THERE'S GENE ALSO
HAS EXPRESSION IN THE LIVER AND
WE HAD TO GO BACK TO THE
TEXTBOOKS AND THINK OF WHAT IT
LOOKS LIKE IN THIS CONTEXT.
WE'RE FORTUNATE TO BE ABLE TO DO
CHEMICAL STRAINING FOR THIS
RECEPTOR PROTEIN IN SUBSEQUENT
SAMPLES AND WE CAN SEE THE GOLD
COLOR HERE IN THE RED IS PICKING
UP THE ANTIBODIES AND ANTIBODY
POSITIVE WHEREAS THE WHITE YOU
DON'T SEE MUCH OF IT.
IN THE RED MOST THE PROTEIN
WE'RE PICKING UP IS WITHIN THE
LYMPHOCYTES THAT ARE THERE.
SO AS WE LOOKED CLOSER INTO THE
GENE IT TURNS OUT THAT IT
ENCODES THE ALPHA IS BETA
RECEPTOR AND THE ROLE IN THE
SPLEEN IS NOT CLEARLY DELINEATED
OR CELLS OR CIRCUMSTANCES BUT
THERE'S A GROWING BODY OF
EVIDENCE THEY CAN MODULATE THE
INNATE IMMUNITY.
SO IT'S A PRETTY DECENT
CANDIDATE.
HOWEVER IT TURNS OUT THERE'S A
BETTER CANDIDATE A LITTLE BIT
AWAY.
SO ABOUT 500K UPSTREAM THERE'S
AN IL12B GENE AND IL12B GENE IS
IN THE SAME TYPO GRAPHICAL
ASSOCIATED DOMAIN ON 4D
CONFIRMATION AND THE GENOME
FOLDS IN THE SAME POCKET AS THE
ENHANCER AND THE COLLABORATOR
WAS FORTUNATE TO LOOK AT THIS IN
PERIPHERAL B CELLS AND COULD
DEMONSTRATE A PHYSICAL INTERACT
BETWEEN THE ENHANCER AND
PROMOTER OF THE IL12B GENE.
SO THAT WAS A POSITIVE THING.
THEN WE WAS ABLE TO SHOW
PROMINENT EXPRESSION IS IN
MONOCYTES AND B CELLS AND LESS
SO IN T CELLS AND OTHER RELATED
CELLS.
THAT MADE IT LOOK LIKE A VIABLE
CANDIDATE ESPECIALLY WHEN YOU
CONSIDER IF YOU THINK ABOUT
WHERE ENHANCERS AND THIS IL12B
GENE IT'S KNOWN TO BE INVOLVED
IN INTRACELLULAR PATHOGEN
RESPONSES.
SO, STIMULATES THE IMMUNE
RESPONSE WITH THE PATHOGENS
INCLUDING MICROPLASMAS AND IN
FACT JUST UP STREAM THERE'S A
GENETIC VARIANT ASSOCIATED WITH
RESISTANCE TO TB IN POPULATIONS
FROM EAST AFRICA SO UGANDA AND
TANZANIA AND PERHAPS IT'S AT THE
CRUX YOU MAY BE PROTECTED FROM
HAVING TB BUT LIKELY TO HAVE
ANOTHER IMMUNIZATION RESPONSE IN
RED CELLS AND THAT'S ALSO
CONSISTENT PERHAPS WITH SOME OF
THE MORE RECENT FINDINGS ABOUT
PRIOR IMMUNIZATION OTHERS HAVE
CONTRIBUTED.
SO WE HAVE BEEN THEN THINKING
HOW WE CAN TAKE THIS FORWARD
MORE AND WE DEVELOPED THE
WORKING MODEL THAT IN THE FACE
OF THIS KIND OF TRANSFUSION YOU
GET THIS INTERACTION THAT LEADS
TO MORE OF P4 AS THE IL12
PROTEIN.
YOU GET MORE OF THE SECRETION.
THAT INFLUENCES THE ANTIBODIES
AND IN INDIVIDUALS NEGATIVE WE
WOULD HAVE THAT OCCURRING.
AND SO WE'VE BEEN TRYING TO
EVALUATE THIS IN TERMS OF AT
LEAST STARTING AND LOOKING AT
THE FUNCTIONAL RELATIONSHIP
BETWEEN THE VARIANT ITSELF,
ENHANCER AND THE GENE AND THE
KEY IS ASCERTAINING INDIVIDUALS
WITH THE VARIANT.
WE'VE BEEN COLLABORATING WITH
DR. MITCHELL AND DR. THEIN TO
IDENTIFY INDIVIDUALS WITH WHOLE
SEQUENCING AND LOOKING AT THOSE
WITH THE VARIANT AND THOSE WHO
DON'T TO LOOK AT THEIR
TRANSFUSION RECORDS AND IDENTIFY
INDIVIDUALS WHO ARE RESPONDERS
AND NON-RESPONDERS AND THEN
AFTER TAKING THEIR SAMPLES THEN
LOOK AT WHAT'S HAPPENING AT THE
LOCUS USING SINGLE CELL AND
SEEING WHAT'S HAPPENING IN TERMS
OF CHROMATIN ACCESSIBILITY AND
LOOKING AT THE EXPRESSION OF THE
GENE AND MEASURE THE PROTEIN
DOWN STREAM AS WELL.
THIS CONTEXT ALSO ALLOWS US TO
THINK ABOUT HOW WE CAN INTRODUCE
TB AS AN ACTOR IN THIS MODEL.
WE'VE BEEN WORKING THROUGH THE
PIPELINE FOR THIS MODEL AND SO
WE CAN AT LEAST GET THE SINGLE
CELLS AND WE HAVE A PIPELINE FOR
BEING TO LOOK AT PBMCs AND
IDENTIFY MONOCYTES FROM THE
SINGLE CELL SEQUENCING AND CAN
STIMULATE THE PBMCs TO SEE
SUFFICIENT ACTIVITY OF IL12 IN
MATERIALS OF EXPRESSION AT 8
HOURS SEEMS TO BE MOSTLY IN M
MONOCYTES AND THEN YOU CAN SEE
PROTEIN PRODUCTION CORRESPONDS
TO THAT AGAIN OCCURRING A LITTLE
BIT LATER THAN THE
TRANSCRIPTIONAL RESPONSE BUT SEE
ROBUST PROTEIN REPRESENTS IN 48
HOURS AT MONOKITE -- MONOCYTES
AND B CELLS AND DOWN THE LINE WE
MAY THINK OF BLOCKING THIS
RESPONSE IN A MORE GENERIC OR
GENERAL APPROACH TO THE
ALLOIMMUNIZATION RESPONSE.
SO WE HAVEN'T QUITE FORGOTTEN
ABOUT THE OTHER GENE IN THAT
REGION AND WE'VE ALSO ARE
BUILDING WAYS OF FIGURING OUT
THE GENE EXPRESSION FOR THAT
GENE AND DOING SINGLE CELL WORK
ON SPLEEN TO COMPLIMENT THE WORK
IN THE PBMCs.
SO I'M GOING TO STOP THERE AND
THEN I'M HAPPY TO TAKE ANY
QUESTIONS.
THANK YOU VERY MUCH.
JUST ONE MINUTE IN CASE FOR
ANYONE IN THE ROOM.
THERE'S NO QUESTIONS IN THE CHAT
BUT JUST A REMINDER IF ANYONE
WANTS TO POSE A QUESTION PRESS
LOVE
LIVE FEEDBACK AND IF NOT WE HAVE
A FIVE-MINUTE BREAK.
THANK YOU, FOR THE GREAT TALK.
WHILE BE CHAIRING THE SESSION
AND MOVING THINGS ALONG.
OUR FIRST SPEAKER IS GOING TO BE
DR. AMANDA BRANDOW.
A PROFESSOR OF PEDIATRICS IN
WISCONSIN IN THE SECTIONS OF
HEMATOLOGY, ONCOLOGY AND BONE
MARROW TRANSPLANTATION AND
DIRECT THE CLINICAL RESEARCH
PROGRAM THERE.
SHE'S A PHYSICIAN SCIENTIST.
SHE LOOKS AFTER CHILDREN WITH
SICKLE CELL DISEASE OTHER
HEMATOLOGIC CONDITIONS AND HER
LAB IS INVESTIGATING THE
UNDERLYING NEUROBIOLOGY OF
INFLAMMATION AND THE MICROBIOME
AND THE TRANSPLANTATION AND
SHE'LL BE WITH US WHEN WE GET TO
THE END.
WE'LL START.
>> TALK ABOUT THE COMPLEXITIES
AND MANAGEMENT OF PAIN IN SICKLE
CELL DISEASE.
MY OBJECTIVES TODAY WILL BE TO
FIRST DESCRIBE THE COMPLEXITY OF
SICKLE CELL DISEASE PAIN
INCLUDING THE TAXONOMY, BIOLOGY
AND THE COMPLEX OF THE
PSYCHOSOCIAL MODEL.
I'LL THEN DISCUSS EVIDENCE-BASED
GUIDELINES FOR TREATMENT OF
SICKLE CELL DISEASE PAIN AND
PHARMACOLOGIC AND
NON-PHARMACOLOGIC TREATMENTS.
I'D LIKE TO OPEN WITH THE
COMPLEXITY OF SICKLE CELL
DISEASE PAIN.
THE PAIN TRAJECTORY ACROSS THE
LIFE SPAN OF INDIVIDUALS WITH
SICKLE CELL DISEASE IS COMPLEX
AND EVOLVES WITH TIME AND THE
YOUNG TODDLER AGE GROUPS THERE'S
MINIMAL PAIN OR ACUTE PAINFUL
EVENTS PRESENT.
THERE'S ACUTE AND INTERMITTENT
PAINT RESULTING IN EMERGENCY
ROOM DEPARTMENT VISITS AND
HOSPITALIZATIONS AND ACUTE
PAINFUL EVENTS ARE MANAGED AT
HOME.
AS PEOPLE AGE INTO CHILDHOOD AND
ADOLESCENCE THE ACUTE
INTERMITTENT PAIN BECOME MORE
FREQUENT AND HOSPITAL VISITS
INCREASE AND IT'S REFRACTORY TO
TREATMENT.
THERE'S INCREASED OPIOID USE AT
HOME, ACUTE PAINFUL EVENTS ARE
SUPER IMPOSED ON THE CHRONIC
DAILY PAIN AND WE SEE AN
INCREASED PREVALENCE OF SICKLE
CELL DISEASE COMORBIDITIES
INCLUDING AVASCULAR NECROSIS AND
LEG ULCERS THAT CONTRIBUTE.
THIS TRANSITION INTEREST ACUTE
TO CHRONIC PAIN IS THE FOCUS OF
A SIGNIFICANT AMOUNT OF RESEARCH
OVER THE LAST DECADE.
THIS FIGURE DISPLAYS A
HYPOTHETICAL MODEL OF SICKLE
CELL DISEASE PAIN I'LL WALK YOU
THROUGH NOW.
THE X AXIS LOOKS AT TIME AS A
VARIABLE WITH EARLY CHILDHOOD ON
THE LEFT AND ADULTHOOD ON THE
RIGHT.
THE Y AXIS THE ORANGE LINE
CHRONIC BASELINE PAIN SENSITIVE
AND THE RED DASH LINE THE
SEVERITY OF ACUTE PAIN AND THE
BLUE LINE THE RELATIVE OPIOID
REQUIREMENT OF TIME.
AS YOU CAN SEE BY DEPICTED IN
THE ORANGE LINE, WE KNOW THAT
THE CHRONIC BASELINE PAIN
SEVERITY INCREASES WITH AGE.
AS YOU SEE THE LINE OVER THE
COURSE OF A LIFE SPAN GOES UP.
WHEN YOU LOOK AT THE RED AND
BLUE LINES TOGETHER THE RED DASH
LINE REPRESENT THE RELATIVE
SEVERITY OF ACUTE PAIN WE SEE
INCREASES OVER TIME AS ONE AGES.
IN THE RECOMBINANT OPIOID
REQUIREMENT THAT ALSO INCREASES
IN PARALLEL WITH THE INCREASE OF
THE RELATIVE SEVERITY OF ACUTE
PAIN AN ADDITION TO THE CHRONIC
BASELINE PAIN SEVERITY.
BECAUSE OF THIS TRANSITION FROM
ACUTE TO CHRONIC PAIN THERE'S
LIKELY A NEUROPATHIC COMPONENT
THAT DEVELOPS OVER TIME AS THE
NERVOUS SYSTEM BECOMES
DESENSITIZED AND CONSIDER
RE-EVALUATION FOR NEURO PATHIC
PAIN WHICH IS ONE OF THE PAIN
TYPES THAT MANIFESTS CLINICALLY
WITH CHRONIC SENSITIZATION OF
THE NERVOUS SYSTEM AND DETERMINE
WHETHER THEY NEED AN ALTERNATIVE
FORM OF TREATMENT.
I'LL NOW GOING TO DISCUSS THE
TAXONOMY OF SICKLE CELL DISEASE
PAIN.
IN THE PAST, SICKLE CELL DISEASE
PAIN WAS FELT TO BE PRIMARILY
ACUTE AND WITHIN A CUTE PAIN
SPACE THERE WAS NON-SICKLE CELL
DISEASE CAUSES OF ACUTE PAIN AND
VASO OCCLUSIVE CRISIS CAUSES OF
ACUTE PAIN.
HOWEVER, THIS MODEL IS QUITE
OUTDATED AND IS NOW BEEN
REPLACED BY THIS VERY COMPLEX
SICKLE CELL DISEASE PAIN MODEL
THAT INCLUDES COMPONENTS OF
ACUTE PAIN AND CHRONIC PAIN.
ACUTE PAIN WE CONTINUE TO HAVE
ACUTE NON-CRISIS PAIN.
WE CONTINUE TO HAVE VASO
OCCLUSIVE PAINFUL EVENTS IN THE
CLASSIC TEACHINGS FOR SICKLE
CELL DISEASE ACUTE PAIN AND HAVE
ACUTE EXACERBATIONS OF CHRONIC
PAIN AND THE CHRONIC PAIN SPAJ
WE HAVE IDENTIFIABLE CAUSES AND
NON-IDENTIFIABLE CAUSES WHICH
I'LL TALK ABOUT MORE DETAIL IN
SUBSEQUENT SLIDES.
AND NO IDENTIFIABLE CAUSE SPACE
WE HAVE COMPONENTS OF NEURO
PATHIC, CHRONIC INFLAMMATORY
PAIN AND CHRONIC NOCICEPTIVE
PAIN AND DRILLING DOWN IN
NEUROPATHIC PAIN CENTRAL
SENSITIZATION I'LL WALK MORE
ABOUT.
-- TALK MORE ABOUT.
THE COMPLEXITY OF THE PAIN
TAXONOMY IS LIKELY DIRECTLY
DIRECTLY RELATED TO HE PAIN
TREATMENT.
THERE'S PAIN PHENOMENON OR
PAIN-RELATED DISEASE HAVE AS
MUCH AS COMPLEXITY OF PAIN
TAXONOMY AS WE SEE IN SICKLE
CELL DISEASE AND THIS LIKELY
GIVES US A CLUE OF WHY IT'S SUCH
A CHALLENGE TO TREAT FOR OUR
PATIENTS.
I'D LIKE TO TALK BRIEFLY ABOUT
THE AAPT DIAGNOSTIC CRITERIA FOR
PAIN FOR SICKLE CELL DISEASE
PUBLISHED AND LIKE TO HONE IN ON
ONE COMPONENT THE DIAGNOSTIC
CORE CRITERIA OF REPORTS OF
ONGOING PAIN PRESENT ON MOST
DAYS OVER THE PAST SIX MONTHS
EITHER IN SINGLE OR MULTIPLE
LOCATION.
THIS IS A KEY COMPONENT OF THE
DEFINITION AND ADAPTED FROM THE
INTERNATIONAL ASSOCIATION FOR
THE STUDY OF PAINS DEFINITION OR
THE IASP DEFINITION OF CHRONIC
WHICH IS PAIN THAT PERSISTS FOR
THREE MONTHS BEYOND THE INCITING
EVENT AND THIS DEFINITION WAS
ADAPTED TO PAIN IN MOST DAYS TO
DEFINE CLINICAL CHRONIC PAIN
WITHIN SICKLE CELL DISEASE.
FURTHER DRILLING DOWN THERE'S
THREE DIAGNOSTIC MODIFIERS AND
ONE CHRONIC PAIN WITH
CONTRIBUTORY DISEASE
COMPLICATIONS AND MIXED TYPE OF
PAIN THAT ENCOMPASS TWO OF
THESE.
UNDERLYING THE COMPLEX TAXONOMY
OF SICKLE CELL DISEASE PAIN IS
FURTHER COMPLEX BIOLOGY THAT
DRIVES SICKLE CELL PAIN AND I
TOUCHED ON THIS BRIEFLY BUT I'D
LIKE TO DRILL DOWN A LITTLE BIT
MORE IN DEPTH NOW.
FIRST, THERE'S NOCICEPTIVE
COMPONENTS LIKELY DRIVEN FROM
THE CLASSIC SICKLE CELL VASO
OCCLUSION THAT CAUSES TISSUE
ISCHEMIA AND REPERFUSION INJURY
AND COMBINENT INFLAMMATION AND
ABNORMALITIES PERIPHERAL NERVES,
BRAIN OR SPINAL CORD THAT
INITIATE TRANSMIT AND SUSTAIN
PAIN SIGNALS AT THE LEVEL OF THE
CENTRAL NERVOUS SYSTEM OR
PERIPHERAL NERVOUS SYSTEM.
THERE'S STRESS MEDIATED
COMPONENTS AND CERTAINLY
PSYCHOSOCIAL CONTRIBUTIONS AND
MENTAL HEALTH ISSUES INCLUDING
DEPRESSION AND ANXIETY THAT CAN
CONTRIBUTE TO PAIN AND CAN BE
EXACERBATED BY LIVING WITH
CHRONIC PAIN.
THIS BIOLOGY IS REALLY IMPORTANT
TO UNDERSTAND IN ORDER TO DRIVE
TARGETED THERAPIES FOR SICKLE
CELL DISEASE PAIN.
AND I WOULD ARGUE THAT TREATING
ALL SICKLE CELL DISEASE PAIN THE
SAME IS LIKE TREATING ALL FORMS
OF ANEMIA WITH THE SAME
APPROACH.
WE REALLY NEED THE ABILITY TO
DIFFERENTIATE IS THE BIOLOGY OF
SICKLE CELL DISEASE PAIN AND
DIFFERENTIATING THIS BIOLOGY IS
LIKELY VERY THERAPEUTICALLY
IMPORTANT AND THE FOCUS OF A LOT
OF RESEARCH GOING ON RIGHT NOW.
IN ADDITION TO THE COMPLEX
TAXONOMY AND THE COMPLEX
BIOLOGY, SICKLE CELL DISEASE
PAIN NEEDS TO BE BOTH THOUGHT
OF, INTERPRETED AND TREATED IN
THE BIO PSYCHOSOCIAL MODEL.
THIS IS DEPICTED ON THE FIGURE
ON THIS SLIDE LOOKING AT THE
BIOLOGICAL FACTORS INCLUDING
HEMATOLOGIC FACTORS AND CHRONIC
ORGAN DAMAGE AND THINKING OF THE
PSYCHOLOGICAL FACTORS
DEPRESSION, ANXIETY AND
HELPLESSNESS AMONG OTHER THINGS
AND THE SOCIOLOGICAL ISSUES
INCLUDING SOCIAL DETERMINATES OF
HEALTH AND STIGMA, TRIGGERS AND
LIFE EVENTS AND DISPARITIES.
EACH CONTRIBUTE INDIVIDUALLY TO
ACUTE PAIN, CHRONIC PAIN AND THE
INTERSECTION BETWEEN THE TWO.
IT'S IMPORTANT TO ALWAYS THINK
OF THIS MODEL AND PUT THE WORK
WE DO IN THE CONTEXT OF THESE
COMPONENTS.
SO IN SUMMARY, SICKLE CELL
DISEASE IS VERY COMPLEX AND
SICKLE CELL DISEASE PAIN IS
COMPLEX AND I'LL SUMMARIZE IT
BRIEFLY.
WE KNOW THERE'S EXTENSIVE
DIVERSE AND COMPLEX CLINICAL
PAIN EXPRESSION IN ACUTE AND
CHRONIC PAIN WHICH I BRIEFLY
DISCUSSED.
THERE'S VERY COMPLEX BIOLOGY.
MANY OF WHICH WE DON'T YET
UNDERSTAND SOME OF WHICH WE DO,
ARE BEGINNING TO UNDERSTAND A
LITTLE BIT ABOUT BUT THERE'S SO
MUCH WORK THAT NEEDS TO BE DONE
IN UNDERSTANDING THE BIOLOGY AND
FINALLY THE BIO PSYCHOSOCIAL
MODEL IS KEY TO INTERPRETING ALL
THESE COFACTORS COLLECTIVELY TO
UNDERSTAND THE CONTEXT OF WHAT
CONTRIBUTES TO THE PAIN THAT OUR
PATIENTS EXPERIENCE.
IN 3, WHERE THEY INTERSECT IS
COMPLEX PAIN TREATMENT.
PROBABLY THE REASON WHY WE HAVE
OFTEN TIMES DIFFICULTY TREATING
PAIN AND EFFECTIVELY TREATING
PAIN AND THE COMPLEXITY OF PAIN
UNDER LIES THE TREATMENT THAT
ALSO NEEDS TO BE COMPLEX IN
ORDER TO EFFECTIVELY MANAGE PAIN
AND IMPROVE THE QUALITY OF LIFE
OF INDIVIDUALS WE TAKE CARE OF.
I DECIDED TO FOCUS ON THE
AMERICAN SOCIETY OF HEMATOLOGY
PUBLISHED FOR THE MANAGEMENT OF
ACUTE AND CHRONIC PAIN AND THIS
FORMS A LARGE MULTIDISCIPLINARY
EXPERT PANEL THAT UNDERWENT AN
EVIDENCE-BASED SYSTEMATIC REVIEW
TO ASSIMILATE AND PUBLISH THE
GUIDELINES.
THERE'S MORE RESEARCH BEING DONE
NOW.
MANY OF WHICH YOU'LL HEAR IN THE
SUBSEQUENT TALKS TO TRY TO
EXPAND THESE GUIDELINES.
BUT I THOUGHT I'D USE THESE AS A
STARTING POINT FOR DISCUSSION OF
THE TREATMENT SINCE I HAD LITTLE
TIME.
THE TREATMENT NEEDS TO BE
THOUGHT OF IN A
MULTIDISCIPLINARY MULTIMODAL
APPROACH AND PAIN COLLEAGUES AND
COLLABORATORS AND PSYCHOLOGISTS
AND PSYCHIATRISTS AND THEIR
CONTRIBUTIONS.
PHYSICAL MEDICINE AND
REHABILITATION AND SOCIAL WORK
AND INTEGRATIVE WORK AND ALL
THESE MULTI-MODAL APPROACHES
CONTRIBUTING TO THE IMPROVEMENT
OF PAIN OF INDIVIDUALS LIVING
WITH SICKLE CELL DISEASE AND THE
CONTEXT OF THEIR FAMILY AND
SOCIAL SUPPORTS.
WE TRIED TO FRAME OUR GUIDELINES
IN THE CONTEXT OF THIS
MULTI-DISCIPLINARY MULTI-MODAL
APPROACH TO PAIN TREATMENT.
THIS IS IT THE HIGH LEVEL
OVERVIEW OF OUR GUIDELINES WHERE
WE LOOKED AT SICKLE CELL DISEASE
PAIN IN THE ACUTE AND CHRONIC
PAIN SPACES.
UNDER ACUTE PAIN SPACE WE LOOKED
AT ANALGESIC DELIVERY IN
LOCATION AND PROTOCOL AND
PHARMACOLOGIC AND
NON-PHARMACOLOGIC THERAPY AND IN
THE CHRONIC PAIN WE LOOKED AT
BOTH NON-OPIOID PHARMACOLOGIC
AND NON-PHARMACOLOGIC THERAPY
AND CHRONIC OPIOID THERAPY AND
CHRONIC TRANSFUSION THERAPY.
WE USED TWO DATA SOURCES
PRIMARILY DIRECT AND INDIRECT
EVIDENCE.
FOR DIRECT EVIDENCE IN
INDIVIDUALS WITH SICKLE CELL
DISEASE WE HAD MINIMAL EVIDENCE
AVAILABLE AND DIPPED INTO THE
INTERDIRECT -- INDIRECT EVIDENCE
AND WE COLLABORATED WITH THE
PRACTICE RESEARCH CENTER WHERE
THEY HELPED US CONDUCT AND
ASSIMILATE THE EVIDENCE REVIEWS
WE USED AS THE BASIS FOR OUR
GUIDELINES.
AS FAR AS THE INDIRECT EVIDENCE
GOES WE REACHED CONSENSUS VIA
SURVEY AND ONLINE PANEL
DISCUSSION ABOUT THE INDIRECT
EVIDENCE AND THE PAIN CONDITIONS
THAT PARALLEL THE ACUTE EVIDENCE
AND LOOKED AT THE SIMILARITY TO
THE BIOLOGY OR THE EXPERIENCE OF
INDIVIDUALS WITH SICKLE CELL
DISEASE DISEASE.
WE UTILIZED ONLY SYSTEMATIC
REVIEWS OR META-ANALYSIS THAT
INCLUDED FIVE OR MORE STUDIES
WHERE SINGLE INDIVIDUAL RESEARCH
STUDIES WERE ACTUALLY NOT USED
AS EVIDENCE FOR THE GUIDELINES
AND WE DOWN GRADE THE INDIRECT
EVIDENCE AS PER THE GRADE
POPULATION FOR DIRECTNESS.
THE COMPOSITION OF OUR PANEL
INCLUDED PEDIATRIC AND ADULT
PROVIDERS AND NURSING
COLLEAGUES, PSYCHOLOGY AND
PSYCHIATRY, REPRESENTATION,
EMERGENCY MEDICINE, A PATIENT
AND PARENT OF A YOUNG CHILD WITH
SICKLE CELL DISEASE AND OUR
METHODOLO
METHODOLOGIST.
WE HAD MAJOR CHALLENGES IN OUR
PANEL.
ONE BEING THE LACK OF DIRECT
EVIDENCE WITH MINIMAL IF ANY
HIGH QUALITY EVIDENCE AND
SIGNIFICANT LACK OF RANDOMIZED
CONTROL TRIALS.
THERE'S CHALLENGES IN HARNESSING
THE INDIRECT DATA AND LEVERAGING
THIS TO IMPROVE OUR IN
GUIDELINES AND DIFFERENTIATING
ACUTE AND CHRONIC PAIN IN THE
LITERATURE IN SICKLE CELL
DISEASE AND THE PEDIATRIC AND
ADULT DATA WERE NOT ALWAYS
AVAILABLE IN PARALLEL IN WHICH
TO USE OUR GUIDELINES.
NOW I'M GOING TO TAKE YOU
THROUGH A FEW GUIDELINES AS AN
EXAMPLE OF PAIN TREATMENT AND
I'LL PRESENT THE QUESTION FIRST
THAT WE OUR EVIDENCE-BASED
SEARCHS ON AND SIMULATION OF THE
DATA AND WE ASKED THE QUESTION
WHETHER PHARMACOLOGIC THERAPIES
IN ADDITION TO OR INSTEAD OF
OPIOIDS OR OTHER USUAL CARE
INTERVENTIONS SHOULD BE USED FOR
THE TREATMENT OF ACUTE PAIN IN
PATIENTS AND ADULTS WITH SICKLE
CELL DISEASE.
ON MY SLIDE ARE TWO
RECOMMENDATIONS THAT WERE
DERIVED FROM THE QUESTION.
THERE'S MORE THERE INCLUDED IN
THE COMPLETE PUBLICATION BUT THE
ONE RECOMMENDATION IS THE USE OF
ANALGESIC DOSING OF KETAMINE AS
AN ADJUNCT TREATMENT FOR PAIN
REFRACTORY OR NOT EFFECTUALLY
TREATED WITH OPIOIDS ALONE AND
THERE'S NO PUBLISHED DATA FOR
REFRACTORY AND WE LEFT THIS OPEN
TO THE DETERMINATION OF THE
CLINICIAN AND PATIENT AND SHARED
DECISION MAKING.
THE RECOMMENDED DOSE IS LISTED
ON MY SLIDE AND THIS WAS BASED
ON LOW CERTAINTY IN THE
STATEMENT OF ARTIFACTS AND
YOU'LL SEE CONDITIONAL
RECOMMENDATION BASED ON LOW
CERTAINTY IN THE EVIDENCE IS A
VERY COMMON THEME.
THE NEXT RECOMMENDATION IN THE
SPACE IS REGIONAL ANESTHESIA FOR
LOCAL OF A PAIN FOR PAIN
REFRACTORY OR NOT EFFECTIVELY
TREATED WITH OPIOIDS ALONE.
DELIVERED VIA A PERIPHERAL NERVE
CATHETER AND COMMON PLACE FOR
ABDOMINAL OR HIP OR LEG PAIN.
THIS OBVIOUSLY HAS TO BE
TECHNICALLY FEASIBLE BASED ON
THE ANATOMIC LOCATION AND HAVE
THE EXPERTISE OF SOMEBODY IN
PAIN MEDICINE TO DELIVER THIS
THERAPY.
AGAIN, THIS IS A CONDITIONAL
RECOMMENDATION.
SHIFTING TO NON-PHARMACOLOGIC
THERAPY FOR ACUTE PAIN WE ASKED
THE QUESTION OF SHOULD
NON-PHARMACOLOGIC THERAPIES BE
USED FOR THE TREATMENT OF ACUTE
PAIN IN CHILDREN AND ADULTS WITH
SICKLE CELL DISEASE.
THERE WERE SEVERAL
NON-PHARMACOLOGIC MODALITIES WE
LOOKED AT EVIDENCE FOR AND
SETTLED ON A VARIETY OF THESE
INCLUDING IN ADDITION TO
PHARMACOLOGIC MANAGEMENT
CONSIDERED INTEGRATING MASSAGE,
YOGA, TENS, GUIDED AUDIO AND
VISUAL RELAXATION.
CONDITIONAL RECOMMENDATIONS
BASED ON LOW CERTAINTY.
MOST HAVE VERY LOW SIDE EFFECT
PROFILES SO WE FOUND IT
IMPORTANT TO PUT THEM FORWARD AS
POTENTIAL INTERVENTIONS FOR ONE
TO CONSIDER TO AUGMENT THE
PHARMACOLOGIC THERAPY PEOPLE
WILL GET OR RECEIVE WHEN THEY'RE
HOSPITALIZED.
SHIFTING NOW INTO THE CHRONIC
PAIN SPACE, WE WERE INTERESTED
IN LOOKING AT NON-OPIOID
PHARMACOLOGIC THERAPY FOR
CHRONIC PAIN.
AND WE ASKED THE QUESTION OF
SHOULD NON-OPIOID PHARMACOLOGIC
THERAPY IN ADDITION OR INSTEAD
OF OPIOIDS OR OTHER USUAL CARE
INTERVENTIONS BE USED FOR
CHILDREN AND ADULT WITH SICKLE
CELL DISEASE IN CHRONIC PAIN
WITH NO IDENTIFIABLE CAUSE
BEYOND SICKLE CELL DISEASE.
SO THIS IS BRINGING US BACK TO
THE AAPT DEFINITION OF CHRONIC
PAIN PUBLISHED AT THE TIME OF
GUIDELINES.
THE SLIDE DEPICTS SOME
INTERVENTIONS THAT CAME FORWARD
IN THIS EVIDENCE-BASED REVIEW
WHERE WE LOOKED AT CHRONIC PAIN
WITH NO IDENTIFIABLE CAUSE
BEYOND SICKLE CELL DISEASE AND
SOME OF THE CONSIDERATIONS CAN
BE SNRI SUCH AS THESE LISTED.
AND THIS RECOMMENDATION WAS
SPECIFICALLY FOR ADULTS.
THERE'S A LACK OF PEDIATRIC DATA
AND THE PANEL FELT THERE ARE
BASED ON THE LACK OF PEDIATRIC
DATA WE COULD NOT SUPPORT A
RECOMMENDATION OF THESE
INTERVENTIONS FOR CHILDREN.
AGAIN, THIS IS A CONDITIONAL
RECOMMENDATION AND THIS WAS
BASED ON INDICT EVIDENCE FROM
THE FIBROMYALGIA FOUNDATION AS
THERE WAS NO EVIDENCE THAT
EXISTED IN THE CONTEXT OF SICKLE
CELL DISEASE SPECIFICALLY.
FINALLY WE WERE INTERESTED IN
LOOKING AT CHRONIC OPIOID
THERAPY OR PERIODIC PERIODIC
THERAPY IN PATIENTS WITH SICKLE
CELL DISEASE WITH CHRONIC PAIN.
A FEW GENERAL COMMENTS ABOUT
CHRONIC PAIN OPIOID THERAPY.
IT WAS IMPORTANT TO THE PANEL TO
CONSIDER A VERY INDIVIDUALIZED
APPROACH TO INITIATING FOR
DISCONTINUING THERAPY AND THIS
WAS BASED ON A BALANCE BETWEEN
RISK AND HARMS AND BENEFITS AND
ALSO CONSIDERING FUNCTIONAL
OUTCOMES FOR THE INDIVIDUAL
THAT'S RECEIVING CHRONIC OPIOID
THERAPY AND THE BENEFIT OVER
TIME.
A RECOMMENDATION IN THIS SPACE
ARE DIVIDED BASED ON THREE
DISTINCT PATIENT POPULATIONS
THAT HAVE A CLEAR PRESENCE OF
CHRONIC, RATHER THAN EPISODIC
PAIN.
SO THE FIRST POPULATION IS
EMERGING AND/OR RECENTLY
DEVELOPED CHRONIC PAIN.
THE PANEL RECOMMENDED AGAINST
THE INITIATION OF CHRONIC OPIOID
THERAPY AND REFRACTORY TO OTHER
MODALITY.
IF SOMEBODY'S ALREADY CHRONIC
OPIOID THERAPY AND FUNCTIONING
WELL AND THOUGHT TO HAVE
PERCEIVED BENEFIT THE PANEL
RECOMMENDED CONTINUATION OF
CHRONIC OPIOID THERAPY.
IF AN INDIVIDUAL'S RECEIVING
CHRONIC OPIOID THERAPY AND
FUNCTIONI IING POORLY THEY
RECOMMENDED AGAINST AND THESE
ARE ALL CONDITION
RECOMMENDATIONS.
WE WERE INTERESTED IN NON
PHARMACOLOGIC THERAPY AND ASKED
WHETHER IT SHOULD BE USED IN
ADDITION TO PHARMACOLOGIC
THERAPY FOR THE TREATMENT OF
CHRONIC PAIN.
"WE SETTLED ON PRIMARILY
FOCUSSING ON COGNITIVE
BEHAVIORAL THERAPY OR CBT AS AN
ADDITION TO OTHER STRATEGIES
THAT WERE CONSIDERED BY THE
PANEL INCLUDING ACCEPTANCE AND
COMMITMENT THERAPY AND MINDFUL
BASED TREATMENT AND COPING
SKILLS AND THERAPY AND THE PANEL
FELT LIKE THESE SHOULD BE USED
IN THE CONTEXT OF COMPREHENSIVE
DISEASE AND PAIN MANAGEMENT PLAN
AND THIS WAS A CONDITIONAL
RECOMMENDATION BASED ON THE
FIBROMYALGIA LITERATURE.
WE HAD A STATEMENT ON SCREENING
FOR MENTAL HEALTH COMORBIDITIES
SPECIFICALLY STATING THAT
PATIENTS SHOULD ROUTINELY
SCREENED AND FOR OTHER
PSYCHOLOGICAL COMORBIDITY.
A GOOD PRACTICE STATEMENT IS NOT
BASED ON A SYSTEMIC REVIEW OF
AVAILABLE EVIDENCE BUT MEANT TO
ENDORSE INTERVENTION OR
PRACTICES THAT THE GUIDELINE
PANEL AGREED HAVE UNEQUIVOCAL
NET BENEFIT AND NOT RECOMMEND BE
USED AND THESE THEREFORE CAN BE
INTERPRETED AS STRONG
RECOMMENDATIONS.
THEN IN THE CONTEXT OF SICKLE
CELL DISEASE THERAPEUTIC OPTIONS
VERY BRIEFLY WE KNOW HIGH --
HIHY
DR
DROXIA AND OTHERS ARE KNOWN AND
CURATIVE THERAPY WITH BONE
MARROW TRANSPLANTATION IS
EFFECTIVE AT DECREASING VASO
OCCLUSIVE PAINFUL EVENTS BUT
THEY'VE BEEN SHOWN TO HAVE
THERAPY EFFECTIVE FOR CHRONIC
PAIN IS CURRENTLY THERE'S NO
ANSWER CURRENTLY TO THAT
QUESTION.
SO IT'S REALLY IMPORTANT TO
CONTINUE TO THINK OF BOTH THE
ASSESSMENT AND TREATMENTS OF
SICKLE CELL DISEASE PAIN IN A
MULTIDISCIPLINARY AND MULTIMODAL
APPROACH OR MODEL WITH THESE
IMPORTANT FACTORS AND A VARIETY
OF INTERVENTIONS AND ASSESSMENT
MEASURES I LISTS INCLUDING
INTEGRATIVE HEALTH APPROACHES
AND UNDERSTANDING SOCIAL
DETERMINATES OF HEALTH AND
PHYSICAL THERAPY, CDT, REGIONAL
ANESTHESIA AND I'LL LEAVE YOU
WITH THIS SUMMARY SLIDE WHICH IS
IDEALLY WHERE WE SHOULD GO OR
STRIVE FOR IN THE CONTEXT OF
PAIN.
WE'VE SHOWN PAIN IS COMPLEX IN
THE ASSESSMENT AND TAXONOMY AND
BIOLOGY.
SO BEING ABLE TO QUANTIFY THE
IMPACT OF PAIN UNDERSTANDING THE
EXTENT OF PAIN ON PATIENT
FUNCTIONING AND BEING ABLE TO
CAREFULLY PHENOTYPE THE PAIN
UTILIZING THE TOOLS IN OUR
TOOLBOX AND BASED ON THIS
COMPLEXITY THINKING ABOUT
PHARMACOLOGIC THERAPY THAT CAN
AND SHOULD BE USED, NON
PHARMACOLOGIC THERAPIES AND IN
AN IDEAL WORLD TARGETING TO
IMPROVE THE QUALITY OF THE LIFE
OF INDIVIDUALS LIVING WITH
SICKLE CELL DISEASE.
THANK YOU FOR YOUR ATTENTION.
AND THANK YOU FOR ALLOWING ME
TO SHARE WITH YOU TODAY.
>> IS THAT YOU ONLINE?
WE'LL GET DR. BRANDOW.
>> HI, PAT.
>> WHAT I'D LIKE TO ASK YOU
MENTIONED ABOUT RESEARCH ON THE
COMPLEXITY OF PAIN MAYBE YOU CAN
GIVE US A REVIEW OF WHAT'S GOING
ON AND SECONDLY IN THE CLINICAL
TRIALS USING PAIN AS THE END
POINT AND I LIKE THE WAY YOU SET
THE COMPLEXITY.
THERE'S ALSO ACUTE PAIN WHICH IS
NON-SICKLE CELL IN ONE OF YOUR
BOXES.
IF YOU'RE LOOKING FOR EFFECTS
AND PRESUMABLY CAUSING VASO
OCCLUSION, SHOULD WE ADD MARK
THAT SUPPORT VASO OCCLUSION
RATHER THAN JUST SAY ACUTE PAIN?
>> GREAT QUESTION THANK YOU FOR
THE EXCELLENT QUESTIONS.
I'LL TAKE THE FIRST ONE ABOUT
THE COMPLEXITY OF PAIN.
AND NOT ONLY LOOKING AT THE RED
CELL ABNORMALITY THAT
INITIATIVES THE PAIN IN YOUNG
LIFE BUT LOOKING AT THE
COMPONENTS OF PAIN FROM THE
CENTRAL NERVOUS SYSTEM AND BRAIN
AND SPINAL CORT AND PERIPHERAL
SYSTEM AND VISCERAL PAIN I THINK
WE KNOW LITTLE ABOUT AND I THINK
THE NEURAL BIOLOGY OF PAIN IS
BASICALLY NEEDS TO BE LOOKED AT
THE ORGAN SYSTEM LEVEL TO TRULY
UNDERSTAND AND WHAT IS DRIVING
IT AMONGST EACH OTHER AND ACROSS
THE LIFE SPAN IS WHAT MAKES IT
SO HIGHLY COMPLEX.
I THINK THERE'S A LOT OF PAIN
BIOLOGISTS THAT STUDIO PAIN
OUTSIDE OF SICKLE CELL DISEASE
THAT NEED TO BE INTERESTED AND
LURE INTO THE STUDY OF SICKLE
CELL DISEASE BECAUSE I THINK
THEY COME AT IT FROM A DIFFERENT
LENS.
I'VE LEARNED IMMENSELY PERFECT
THE COLLEAGUES THAT LOOK AT
LABORATORY MODELS.
THINKING ABOUT PAIN AND SICKLE
CELL DISEASE NOT JUST AS A
HEMATOLOGIC PROBLEM BUT AS A
GLOBAL SYSTEMS BASED APPROACH
AND HONING IN ON EACH SYSTEM AND
THE CONTRIBUTION OF PAIN I THINK
IS WHERE WE ABSOLUTELY NEED TO
CONTINUE TO GO WITH THE WORK
WE'RE DOING.
TO ANSWER YOUR SECOND QUESTION
ABOUT END POINTS FOR CLINICAL
TRIALS, I THINK WE NEED TO LOOK
AT A PATIENT-REPORTED OUTCOME OF
PAIN.
THE REPORT OF PAIN IS THE GOLD
STANDARD IS ASKING THE PATIENT
NOT NECESSARILY A BIOLOGICAL
CORRELATE TO SAY THEY ARE IN
PAIN BUT I THINK THERE'S IMMENSE
VALUE IN LOOK AT THE TWO
TOGETHER AND AS A COMPOSITE END
POINT OF CAN WE VALIDATE
PLASMA-BASED BIOMARKER IN THE
COMPANIONSHIP WITH A
PATIENT-REPORTED OUTCOME SO WE
KNOW THEY GO TOGETHER WHEN X
GOES UP PAIN IS WORSE.
LOOKING AT THEM TOGETHER THINK
IS REALLY IMPORTANT.
>> THANK YOU, WE'LL MEDE --
NEED TO MOVE ON TO THE NEXT.
>> I'LL BE QUICK.
EXCELLENT TALK.
I WANT TO TALK ABOUT LIDOCAINE.
I DID NOT SEE THAT IN THE
OUTLINES.
OUR HOSPITAL JUST GOT LIDOCAINE
AS AN ADJUVANT AND RECENT DATA
SUPPORTING IT AND I WANT YOUR
THOUGHTS ON THAT.
EXCELLENT TALK.
THANK YOU.
>> THANK YOU SO MUCH FOR THE
QUESTION.
WHEN WE WROTE THE GUIDELINES
THEY WERE PUBLISHED IN 2020 AND
THE LITERATURE REVIEW TOOK PLACE
LONG BEFORE THAT AND WE SHARED
THE CONCERN WE NEED TO UPDATE
THEM AS SOON AS POSSIBLE.
AT THE TIME WE RECOMMENDED FOR
OPIOID REFRACTORY THE INITIATE
OF KETAMINE AND DID NOT INCLUDE
LIDOCAINE BECAUSE THE LITERATURE
AT THE TIME DIDN'T POINT TO THAT
DIRECTION HOWEVER, WE'RE IN THE
PROCESS OF DOING ANOTHER
LITERATURE SEARCH AND UPDATING
THOSE GUIDELINES.
SO WE WOULD LOVE TO LOOK AT
LIDOCAINE AND IF YOU HAVE
EVIDENCE FROM YOUR OWN
INSTITUTION IT WOULD BE
FANTASTIC TO ASSIMILATE AND PUT
OUT IN THE LITERATURE TO LEARN
FROM YOUR EXPERIENCE BECAUSE IT
WORKS THROUGH A DIFFERENT
PATHWAY AND THERE'S REASONS TO
BELIEVE IT WOULD BE EFFICACIOUS
OR EFFECTIVE IN TREATING SICKLE
CELL PAIN FOR CERTAIN
INDIVIDUALS.
>> WE'LL MOVE ON TO OUR NEXT
SPEAKER, SUSANNA CURTIS ON
CANNABINOIDS AND OPIOIDS.
ALSO LOOKING AT THE ROLE OF
DYSFUNCTIONAL INFLAMMATION AND
ORGAN DAMAGE IN PEOPLE WITH
SICKLE CELL DISEASE AND
DEVELOPING CHRONIC PAIN AND
INTERESTED IN EXAMINING THE
UTILITY OF CANNABINOIDS FOR
TREATING CHRONIC PAIN AND THAT'S
WHAT WE'LL HEAR ABOUT TODAY.
>> THANK YOU TO THE ORGANIZERS
AND FOR THE INVITATION TO SPEAK.
I'LL SPEAK ABOUT CANNABINOIDS
VERSUS OPIOIDS.
IT'S HARD TO SAY THEY'RE VERSE.
WHEN WE TALK ABOUT TREATING PAIN
WE NEED TO LOOK AT THEM AND TALK
ABOUT A COMPARISON.
WE'LL TALK ABOUT THEM AS
MULTI-RECEPTORS AND THEIR USE IN
PAIN AND ADVERSE EFFECTS AND HOW
DO WE USE THEM AND EVIDENCE DO
WE HAVE OF THEIR USE IN SICKLE
CELL DISEASE.
SO BOTH THE OPIOID AND THE
CANNABINOID SYSTEM ARE
ENDOGENOUS CENTRAL TO OUR NEURAL
LOGICAL DEVELOPMENT AND USED
BOTH IN PAIN AND OTHER THINGS
LIKE APPETITE AND SLEEP AND
REWARD.
SO ON THE LEFT YOU CAN SEE THE
INDIGENOUS OPIOID SYSTEM IN THE
CENTRAL NERVOUS SYSTEM THOUGH IT
HAS OTHER LOCATIONS AS WELL.
THE PRIMARY RECEPTORS ARE THE
KAPPA RECEPTORS.
THOSE THE ONES WE KNOW MOST
ABOUT AND TEND TO TARGET DRUGS.
I'LL GIVE YOU ONE OF MY FAVORITE
FUN FACTS ABOUT THE SYSTEM YOU
CAN STIMULATE INDIGENOUS OPIOIDS
WITH THE PEDIATRICIANS THAT'S
WHY THEY GIVE SUGAR WATER TO
BABIES FOR CIRCUMCISIONS AND
WHEN WE ARE SORE YOU CAN
CONSIDER DESSERT AND THE
CANNABINOID SYSTEM IS PERIPHERAL
AND HAS CANNABINOID RECEPTOR 1
AND 2.
CANNABINOID RECEPTOR 1
NEUROLOGIC AND IN THE PERIPHERAL
SYSTEM AND THE RECEPTOR THAT
DOES WHAT WE THINK ABOUT LIKE
PAIN, APPETITE, ANXIETY AND
SLEEP.
CANNABINOID RECEPTOR 2, YOU CAN
SEE IT'S LOCATED IN CNS AND
LOCATED ON THE MICROGLIA THE
IMMUNE CELLS OF THE NERVOUS
SYSTEM AND HAS THE PRIMARY
LOCATIONS AND IMMUNOLOGIC
RECEPTORS.
SO WHERE ARE WE IN DRUG
DEVELOPMENT
>> WHEN IT COMES TO OPIOIDS WE
HAVE BEEN DOING A LOT OF DRUG
DEVELOPMENT FOR A LONG TIME
THAT'S LED TO WONDERFUL THINGS
AND SOME REALLY SAD THINGS AS
WELL.
BUT WE HAVE REALLY DONE A NICE
JOB UNDERSTANDING THESE THREE
PRIMARY RECEPTORS UNDERSTANDING
THEIR ROLE AND UNDERSTANDING HOW
TO TARGET THEM.
SO THIS IS A LIST ACTUALLY OF
OVER THE COUNTER OPIOIDS.
SO WE CAN SEE NOT ONLY CAN WE
USE OPIOID FOR THINGS LIKE PAIN
BUT USE CODING TO TARGET COUGH
AND AS ANYBODY WHO TREATS SICKLE
CELL DISEASE IN THE HOSPITAL
KNOWS WE HAVE MANY NARCOTICS TO
TARGET THESE RECEPTORS.
WHEN IT COMES TO DRUG
DEVELOPMENT IN OPIOIDS WE HAVE
REALLY COME A LONG WAY AND HAVE
A NICE UNDERSTANDING OF THE
SYSTEM AND HAVE A LOT OF
DIFFERENT PHARMACOLOGIC OPTIONS
TO TARGET IT.
THAT'S NOT SO WITH CANNABINOIDS.
WE HAVE A MUCH MORE SHALLOW
UNDERSTANDING HOW TO STIMULATE
THE RECEPTORS AND HAVE VERY FEW
FDA APPROVED DRUGS TO USE.
THIS IS THE ENTIRE LIST HERE.
WE HAVE TWO FORMS OF THC.
THC IS WHAT WE THINK OF AS THE
PRIMARY ACTIVE INGREDIENT IN
CANNABIS A CANNABINOID RECEPTOR
1 AND 2 PARTIAL AGONIST.
YOU GET STIMULATION OF BOTH
RECEPTORS THERE.
SO THIS IS PROVED FOR THE OF
NAUSEA AND WEIGHT GAIN.
AND WE HAVE ONE FORMULATION OF C
-- CBD WHAT YOU SEE IN ALL THE
BAKE STORES WALKING DOWN THE
VOTE AND TRY TO SUGGEST IT FOR
USE FOR EVERYTHING UNDER THE SUN
INCLUDING USE FOR YOUR PETS AND
WHAT DO WE KNOW ABOUT THIS?
IT'S A RECEPTOR 1 AND 2 AN --
ANTAGONIST AND WE DON'T KNOW
WHAT RECEPTORS IT'S TARGETING
BUT WE DO KNOW IS IT'S QUITE
ANTI-INFLAMMATORY AND SEEMS TO
CALM DOWN THE INMATE IMMUNE
SYSTEM AND SO WE HAVE ONE FDA
APPROVED CBD FORM USED FOR RARE
SEIZURE DISORDERS.
AND THERE'S AN ORAL SPRAY THAT
CONTAINS CBD AND THC NOT
APPROVED IN THE UNITED STATES
BUT APPROVED IN EUROPE AND GIVEN
FOR THE TREATMENT NEUROPATHIC
PAIN IN MULTIPLE SCLEROSIS.
WE HAVE SOME CANNABINOIDS IN A
REGULATED FORM BUT WE'RE FAR
BEHIND WHERE WE HAVE COME WITH
OPIOIDS.
WHAT ABOUT USE IN DIFFERENT PAIN
TYPES?
AS DR. BRANDOW ILLUSTRATED WE
KNOW WHEN IT COMES TO PAIN
SICKLE CELL DISEASE THERE'S MANY
CAUSES AND THERE'S A VARIETY OF
BIOLOGIES BEHIND THOSE CAUSES.
WHAT WE MIGHT DO TO TREAT PAIN
IN ONE INDIVIDUAL MAY BE VERY
DIFFERENT THAN WHAT WE'D DO FOR
ANOTHER INDIVIDUAL.
SO WHEN IT COMES TO ACUTE PAIN
THAT IS OF COURSE OUR CLASSIC
SICKLE CELL DISEASE CRISIS BUT
COULD BE OTHER SUDDEN TISSUE
DAMAGE WE KNOW OPIOIDS ARE
INCREDIBLY EFFECTIVE FOR ACUTE
PAIN AND ARE OUR BEST TREATMENT
FOR WHEN SOMEONE COMES IN WITH
PAIN WITH TISSUE DAMAGE.
CANNABINOIDS IN TERMS OF ACUTE
PAIN THE STUDIES ARE MIXED SOME
SHOW BENEFIT AND SOME DON'T WE
CAN'T SAY IT'S SO EFFECTIVE
THERE JUST YET.
BUT WHEN IT COMES TO CHRONIC
PAIN I THINK WE HAVE A LITTLE
BIT OF THE OPPOSITE SITUATION.
STUDIES COMPARING OPIOIDS TO
PLACEBO HAVE SHOWN IT DOES HAVE
SOME BENEFIT IN CHRONIC PAIN BUT
COMPARED TO OTHER NON-OPIOID
MEDICATIONS LIKE GABA PENT NOIDS
THEY SHOW OPIOIDS REALLY AREN'T
MORE EFFECTIVE THAN THOSE
MEDICATIONS BUT IN THE MEANWHILE
THE ADVERSE EFFECTS ARE MUCH
MORE CONCERNING.
YOU'RE TREATING CHRONIC PAIN
MAYBE IT'S NOT YOUR GO-TO AND
STUDIES HAVE SHOWN THERE SEALS
TO BE A TRUE BENEFIT IN PEOPLE
WITH DAILY PAIN FOR USE IN
CANNABINOIDS.
SOME SPECIFIC PAIN TYPE UNDER
THAT FOR NEUROPATHIC PAIN, PAIN
FROM NERVE DAMAGE AND OPIOIDS
AGAIN AREN'T REALLY EFFECTIVE
FOR TREATING NEUROPATHIC PAIN
AND CANNABINOIDS HAVE SHOWN A
BENEFIT IN NEURO PATHIC PAIN AND
PATIENTS WITH SICKLE CELL
DISEASE IT CAN BE IMPORTANT.
INFLAMMATORY PAIN.
THOSE OF US WHO HAVE SORE ARM
AFTER OUR COVID SHOT KNOW
INFLAMMATION EVEN ABSENT OF
TISSUE OR NERVE DAMAGE CAN CAUSE
PAIN IN AND OF ITSELF AND SICKLE
CELL DISEASE A DISEASE OF
CHRONIC INFLAMMATION HAS
INFLAMMATION CONTRIBUTING TO
PAIN.
NOW OPIOIDS ARE ACTUALLY
PRO-INFLAMMATORY.
OPIOIDS LIKE MORPHINE WILL
TRIGGER THE MAIN ACTOR --
ACTIVATORS AND WILL CAUSE
INFLAMMATION WHERE IS
CANNABINOIDS ARE AN
ANTIINFLAMM
ANTIINFLAMMATORY --
ANTI-INFLAMMATORY AND WE DON'T
HAVE THE DATA YET.
AND PAIN SENSITIZATION IS
IMPORTANT IN SICKLE CELL DISEASE
WE KNOW OPIOID CAN CAUSE OPIOID
HYPER ALGESIA AND THEMSELVES CAN
BE A PAIN OF PAIN SENSITIZATION
AND CANNABINOIDS HAVE BEEN KNOWN
TO REDUCE THRESHOLDS FOR PAIN
AND INCREASE PAIN TOLERANCE AND
DECREASE PAIN UNPLEASANTNESS AND
THERE'S A ROLE BUT WE NEED MORE
RESEARCH TO BE DONE.
AND HOW ABOUT ADVERSE EFFECTS.
SO BOTH OPIOIDS AND CANNABINOIDS
CAN LEAD TO SLOWER REACTION TIME
AND THEY CAN BOTH CAUSE EUPHORIA
AND DROWSINESS AND OF COURSE
USING THEM IN COMBINATION COULD
INCREASE THE SIDE EFFECTS.
THEY CAN BOTH CAUSE
CARDIOVASCULAR AFFECTS,
HYPOTENSION AND TACHYCARDIA.
BOTH CAUSE SIDE EFFECTS.
OPIOIDS TEND TO REDUCE APPETITE
AND CANNABINOID INCREASE
MOTILITY SO THEY CAN CAUSE
DIARRHEA AND ARE APPETITE
STIMULATED.
THEY ACCURATE TOLL LIGHT
RECEPTOR 4 SO WHEN PATIENTS
COMPLAIN THEY'RE VERY ITCHY IT'S
BECAUSE ALL THE HISTO MINES AND
THEY CAN CAUSE HYPER GONADISM
USED OVER TIME.
IN TERMS OF RESPIRATORY EFFECTS
WE KNOW THEY CAN CAUSE
RESPIRATORY DEPRESSION.
CANNABINOID CAN CAUSED
RESPIRATORY EFFECTS IN INHALED
MANNER AND IT IN CAN BE
ASSOCIATED WITH COUGH AND THAT'S
SOMETHING WE DON'T WANT TO
SUPPORT AND TALK TO THEM ABOUT.
CANNABINOIDS HAVE A UNIQUE
PROPERTY AND SEEM TO INCREASE
RISK OF PSYCHOSIS AND RATE IS 1
OF 100 BUT IN CANNABIS USERS
IT'S 2 OUT OF 100 BUT SEEMS TO
BE HIGHER IN PEOPLE WITH
PREDISPOSITION AND OVERDOSE.
BOTH CAN CAUSE OVERDOSE AND
THOUGH WE KNOW PATIENTS WITH
SICKLE CELL DISEASE DO HAVE
LOWER OPIOID RATES IT'S NOT
SOMETHING WE CAN IGNORE.
CANNABINOID OVERDOSE CAN CAUSE
DELIRIUM BUT IS NON-FATAL AND
BOTH CAN CAUSE LEGAL TOXICITY
AND I'VE LOOKED AT VERSIONS AND
BUT BOTH EXIST IN UNREGULATED
FORMS AND PEOPLE CAN PURCHASE
THEM MORE LEGALLY NOW THAN 10
YEARS AGO BUT MAYBE MORE IN 10
YEARS FROM NOW AND ILLEGALA
ILLEGALALITY -- ILLEGALITY AND
MOST PEOPLE WITH SICKLE CELL
DISEASE ARE PEOPLE OF COLOR AND
THEY'RE FOUR TIMES MORE LIKELY
TO BE ARRESTED FOR CANNABIS USE
AND PROSECUTED MORE HARSHLY SO
IT'S A CONCERN FOR OUR PATIENTS.
AND FINALLY WHAT ABOUT FINANCIAL
TOXICITY?
AGAIN, WE'VE DONE A LOT MORE
DRUG DEVELOPMENT FOR OPIOIDS.
WE HAVE MORE OPTIONS AND THINGS
TO PRESCRIBE PATIENTS AND WHEN
WE PRESCRIBE THEM FOR THE PART
PATIENTS AREN'T PAYING A LOT OF
OUT OF POCKET AND CANNABINOIDS
ARE FEDERALLY ILLEGAL MEANING NO
INSURANCE COMPANY WILL COVER IT
SO EVEN IF YOU HAVE A PATIENT ON
MEDICAL CANNABIS IT WILL BE OUT
OF POCKET AND THAT CAN ADD UP
QUICKLY.
ON AVERAGE AN OUNCE OF CANNABIS
IS ABOUT $300 AND AN OUNCE OF
CANNABIS DEPENDING CAN MAKE
ROUGHLY ABOUT 60 CANNABIS
CIGARETTES.
AGAIN, WE DON'T WANT TO
ENCOURAGE SMOKING BUT TO GIVE
YOU AN IDEA SOMEONE CAN SPEND A
LOT OF MONEY FOR DAILY PAIN AND
THIS CAN BECOME A BIG PROBLEM
FOR PATIENTS.
SO WHAT DO WE KNOW ABOUT SICKLE
CELL DISEASE?
I WON'T GO INTO THIS IN TOO MUCH
DETAIL BECAUSE DR. BRANDOW DID A
LOVELY JOB GOING OVER THE
GUIDELINES BUT FOR ACUTE PAIN WE
KNOW OPIOID THERAPY SHOULD BE
GIVEN RAPIDLY IDEALLY WITHIN THE
FIRST HOUR.
THERAPY SHOULD BE TAILORED WE
WANT AN INDIVIDUAL PAIN PLAN IN
PARTNERSHIP WITH THAT PATIENT
AND OTHER THERAPIES AS WELL.
CHRONIC PAIN IS MORE
COMPLICATED.
AS DR. BRANDOW STATED, CERTAINLY
WE WANT TO START WITH OTHER
AGENTS, SSRIs, PHYSICAL THERAPY,
OTHER OPTIONS BUT IF THEY
HAVEN'T BEEN EFFECTIVE FOR A
PATIENT WE CAN CONSIDER STARTING
CHRONIC OPIOID THERAPY AND
THEY'RE ALREADY ON IT WE SHOULD
WORK WITH THE PATIENT TO SEE HOW
IT'S WORKING FOR THEM AND WHAT
TO DO ABOUT IT.
NOW, WHEN IT COMES TO
CANNABINOIDS WE HAVE LESS DRUGS
AND HAVE DONE LESS RESEARCH.
SO THE AMERICAN SOCIETY OF
HEMATOLOGY SAID IN THEIR 2020
GUIDELINES IT'S A RESEARCH
PRIORITY THE BENEFITS AND RISK
OF CANNABINOIDS IN SICKLE CELL
DISEASE BE EXAMINED.
WHAT DO WE KNOW?
WE KNOW FROM MOUSE MODELS
CANNABINOID RECEPTOR 1 AND 2 IN
MICE WILL REDUCE INFLAMMATION
WHICH WHEN IT COMES TO SICKLE
CELL DISEASE HAS IMPORTANT
INDICATIONS AND CANABIDIOLE
REDUCES INFLAMMATION.
AND CHRONIC PAIN IS REPORTED AND
THAT'S HIGH COMPARED TO THE
GENERAL POPULATION BUT NOT HIGH
FOR OTHER POPULATIONS OF CHRONIC
PAIN.
THIS IS PRETTY TYPICAL FOR ANY
CHRONIC PAIN POPULATION.
RECEIVING MEDICAL CANNABIS
COMPARED TO PATIENTS THAT ASKED
FOR CERTIFIED IS RELATED TO
SUBSEQUENT REDUCTION IN
ADMISSIONS THESE ARE
CROSS-SECTIONAL STUDIES NOT
PROSPECTIVE.
THERE WAS FIVE DAYS OF INHALED
THC, CBD COMPARED TO PLACEBO.
IT'S AMAZING THE RESEARCHERS
WERE ABLE TO COMPLETE THE STUDY
BECAUSE THERE'S A LOT OF
CHALLENGES TO DOING PROSPECTIVE
CANNABINOID STUDIES.
THE STUDY SHOWED AN IMPROVEMENT
UP MOOD FROM PATIENTS WHO
INHALED THE CANNABIS BUT WASN'T
STATISTICALLY SIGNIFICANT
TOWARDS IN IMPROVEMENT IN DAILY
PAIN BUT IT WAS ONLY A FIVE-DAY
STUDY.
WHEN IT COMES TO MODULATING
CHRONIC PAIN WE THINK OF
MEDICINES NEEDING MONTHS NOT
DAYS.
AND I WILL THANK THE NHLBI FOR
FUNDING MY CASE STUDY WHICH IS
EXAMINING ORAL THC THIS
MEDICATION FOR EIGHT WEEKS AND
EVALUATING THE EFFECT OF CHRONIC
PAIN AND OTHER MARKERS.
A LOT OF EVIDENCE WE NEED BUT I
THINK THERE ARE THINGS GOING ON.
SO MAYBE IN THE NEXT DECADE WE
CAN START TO CATCH UP WITH OUR
DRUG DEVELOPMENT AND
UNDERSTANDING OF CANNABINOIDS.
IN CONCLUSION, WHEN IT COMES TO
ACUTE PAIN IN SICKLE CELL
DISEASE I THINK OPIOIDS SHOULD
BE UTILIZED AND THEY'RE A GREAT
TREATMENT FOR THAT.
WHEN IT COMES TO CHRONIC PAIN
THEY SHOULD BE MORE SECONDARY.
THEY'RE ON THE LIST BUT WE NEED
TO THINK OF OTHER THINGS.
CANNABINOIDS MAY HAVE A ROLE IN
CHRONIC PAIN AND SICKLE CELL
DISEASE BUT WE NEED MORE WORK IN
DRUG INVESTMENT AND RANDOMIZED
STUDIES BEFORE WE UNDERSTAND THE
BENEFIT AND RISK OF THE USE.
AND ULTIMATELY ALL DECISIONS
NEED TO BE MADE IN PARTNERSHIP
WITH THE PATIENTS AND ALL
DECISIONS WITH CANNABINOID
SHOULD BE MADE WITH HARM
REDUCTION IN MIND.
WHEN IT COMES TO THE
CONVERSATIONS WITH THE PATIENT
USING CHRONIC OPIOID THERAPY AND
MAYBE THERE'S A CONCERN ABOUT
THEIR FUNCTION PLEASE REMEMBER
SUDDEN REDUCTION AND SUDDENLY
CUTTING OFF SOMEBODY'S OPIOID
SUPPLY WHEN THEY'RE USING IT
CHRONICALLY IS ASSOCIATED WITH
OVERDOSE AND WE NEED TO WORK IN
PARTNERSHIP WITH OUR PATIENTS.
ONLY THE OTHER SIDE FOR THE
PATIENTS REPORTING CANNABIS IS
HELPFUL FOR THEIR PAIN, IF WE
GIVE THEM ACCESS TO MEDICAL
CANNABIS, THOUGH IT'S NOT AS
REGULATED AS AN FDA APPROVED
PRODUCT IT CAN BE USED IN EDIBLE
FORM AND GIVING THEM ACCESS TO
SOMETHING THAT IS REGULATED SO
AT LEAST WON'T HAVE THE RISK OF
BEING LACED WITH DANGEROUS S OR
THE LEGAL RAISING OF OBTAINING
SOMETHING ILLEGAL.
SO THANK YOU FOR YOUR ATTENTION
AND HAPPY TO TAKE ANY QUESTIONS.
>> MY SUGGESTION WOULD BE TO
STUDY MORE IN DWEFT --
INGESTIBLES OR TRANS DERMAL FOR
CHRONIC PAIN.
I FIND IT HELPFUL FOR ME AND
WOULD CERTAINLY LIKE TO SEE THE
RESEARCH DONE FOR INGESTIBLES OR
TRANS DERMALS.
>> ABSOLUTELY.
THANK YOU FOR THAT EXCELLENT
COMMENT.
AND SMOKE ONLY LASTS ABOUT AN
HOUR AND INGESTIBLES CAN LAST
FROM EIGHT TO 12 HOURS.
I THINK WHEN WE ARE THINK OF
TREATING CHRONIC PAIN AN
INGESTIBLE IS POTENTIALLY MORE
EFFECTIVE.
THANK YOU FOR THAT.
>> DR. CURTIS THANKS FOR YOUR
NICE TALK AND HARD WORK IN
SOLVING THE RIDDLE.
GOOD LUCK TO YOU.
I WONDER IF YOU CAN COMMENT ON
THE INCREASED RATES OF PSYCHOTIC
EPISODES IN PEOPLE EXPOSED TO
MARIJUANA AND THIS IS A CONCERN
AND HAVE MORE THAN ONE ANECDOTE
OF THIS TRANSPIRING IN OUR WORK
AT JOHNS HOPKINS.
>> YES, IT'S ABSOLUTELY A
CONCERN.
IT DOES SEEM THAT ONE OF THE
SIDE EFFECTS OF PARTICULARLY THC
IS THIS RARE ACUTE PSYCHOTIC
EPISODE.
IT DOES SEEM LIKE MANY OF THESE
EPISODES OR AT LEAST THERE'S
MORE LIKELY TO HAPPEN IN
PATIENTS THAT HAVE ALREADY HAD
PREVIOUS PSYCHOTIC EPISODES OR
LEADS TO THEIR FIRST PSYCHOTIC
BREAK.
SO WHAT I WOULD SAY IS IN ANY
PATIENT WHO HAD PREVIOUS HISTORY
OF PSYCHOSIS OR CONCERN WITH
PARANOIA OR PSYCHOSIS IN THE
PATIENT I'D RECOMMEND THEM TO
NOT USE THC PRODUCTS.
IN TERMS OF PATIENTS THAT DON'T
HAVE THAT HISTORY, I THINK
UNFORTUNATELY IT'S A RARE BUT
DEVASTATING SIDE EFFECT.
>> SPEAKING WITH MY PSYCHIATRIST
HAT ON FOR 10 SECONDS, THE
LONGER TERM WORRY ABOUT
MARIJUANA SEEMS TO BE THERE'S A
LOT OF DIFFERENT MEDICINES IN
DRUGS THAT CAN CAUSE PSYCHOSIS
BUT WHEN IT'S CAUSED BY
MARIJUANA IT SEEMS TO BE MORE
LOOKLY CHRONIC AND WHAT WE HAVE
TO BE MOST WORRIED ABOUT.
>> LET'S MOVE ON, SHALL WE.
NEXT UP, WE HAVE DR. ZENA
QUEZADO AND I MUST APOLOGIZE BUT
I'M GOING TO NEED HELP IN THE
PRONUNCIATION BECAUSE MY
PORTUGUESE IS NON-EXISTENT.
CHAIR OF ATHESIOLOGY IN THE
DEPARTMENT OF NATIONAL INSTITUTE
OF HEALTH CLINICAL CENTER AND
RECEIVED HER M.D. IN BRAZIL AND
TRAINED IN CRITICAL MEDICINE AND
INTERNAL MEDICINE AND ANESTHETIC
PEDIATRIC AND PAIN MANAGEMENT
AND DR. QUEZADO WILL TALK TO US
ABOUT KETAMINE.
>> THANK YOU.
FIRST I'D LIKE TO THANK THE
ORGANIZERS FOR THE OPPORTUNITY
TO SPEAK TO YOU TODAY IN THIS
GREAT CONFERENCE.
SO, I AS DR. CARROLL
MENTIONED -- BY THE WAY, YOU DID
A GREAT JOB WITH YOUR
PORTUGUESE, ABOUT THE RULE OF
KETAMINE IN SICKLE CELL DISEASE.
SO WE'RE GOING TO REVIEW THE
RATIONALE FOR THE USE OF
KETAMINE TO TREAT SICKLE CELL
DISEASE AND BRIEFLY LOOK AT THE
GUIDELINES AND REVIEW THE
EVIDENCE IN SUPPORT ITS USE.
A LITTLE BIT ABOUT THE DRUG IT
WAS GENERATED IN 1962 LOOKING
FOR AN ANALOG OF PCP WITH A BETA
SIDE EFFECT PROFILE.
HE DESIGN WHAT WE USE AS
KETAMINE WHICH IS BASICALLY A
MIXTURE OF S AND R KETAMINE AND
THAT'S WHAT WE USED CLINICALLY
THESE DAYS.
IN 1970 THE FDA APPROVED
KETAMINE AS AN ANESTHETIC AND
USED IN THE BATTLEFIELD THROUGH
THE VIETNAM WAR.
IN THE '80s WE STARTED TO LEARN
ABOUT ITS EFFECT ON THE
RECEPTOR.
IN 2000 THE INVESTIGATIONAL USE
OF THE DRUG AS AN ANTIDEPRESSANT
AND OTHER PSYCHIATRIC ILLNESSES
AND IN 2019 THE FDA APPROVED F
KETAMINE FOR THE TREATMENT OF
TREATMENT-RESISTANCE DEPRESSION.
SO WHAT IS THE RECEPTOR THAT
CAUSES SUCH A BIG PROBLEM?
IT'S A GLUTAMATE RECEPTOR AND
ONCE IT'S ACTIVATED BY GLUTAMATE
IT GOES TO POST SYNAPTIC NEURONS
AND LEADS TO DESENSITIZATION OF
NOCICEPTIVE NEURON AND HAS A
ROLE IN THE MAINTENANCE OF
OPIOID TOLERANCE AND APART FROM
THE GLUTAMATE SITE IT'S A
NON-COMPETITIVE ANTAGONIST AN
BECAUSE OF -- IN ADDITION TO AN
NDA RECEPTOR AFFECT IT HAS
AFFECT IN OTHER SYSTEMS LIKE
OTHER RECEPTORS AND DOPE MIN
MINNER -- DOPAMINEERGIC
RECEPTORS.
GIVEN THE ROLE IN ANALGESIA THE
CIRCUMSTANCES IN SOME PATIENTS
WITH SICKLE CELL DISEASE PAIN
SHOW THE DRUG MAKES SENSE TO USE
IT AND WHAT OCCURS IS HERE IS A
CARTOON ILLUSTRATING THE
NOCICEPTOR CENTRAL TERMINAL IN
THE SPINAL CORD AND YOU HAVE ALL
THE NEURO TRANSMIT ETERS YOU SE
THE RECEPTOR CLOSED HERE.
THIS IS ADDRESSED.
KNOW WHEN HAVE YOU THE
NOCICEPTIVE INPUTS YOU RELEASE
OF THE TRANSMITTER AND
ACTIVATION OF A SLEW OF
RECEPTORS AND GLUTAMATE RECEPTOR
AND WHAT YOU SEE IS ENTRY IN THE
POST SYNAPTIC NEURONS AND THE
PROTEIN KINASE AND A WIND UP OF
THIS PHENOMENAL LEADING TO
CENTRAL SENSITIZATION.
IT'S A SIMPLISTIC WAY OF SAYING
IT'S WHAT WE KNOW HAPPENS.
THE RECEPTOR ALSO HAS A ROLE IN
OPIOID TOLERANCE WITH CHRONIC
USE OF OPIOIDS OF MORPHINE WITH
THE OPIOID RECEPTORS IN THE
CONSTANT INPUT OF NOCICEPTIVE
INPUT INTO THE MDA RECEPTOR AND
YOU HAVE THE CROSS-TALK LEADING
TO SIGNIFICANT BIO CHANGES I
DON'T HAVE TIME TO GO INTO BUT
INCREASING TO ACTIVATION OF
MICROGLIA ALL BELIEVED TO PLAY A
ROLE IN OPIOID INTOLERANCE AND
REGARD TO HYPERALGESIA THE
OPIOID MOLECULE IN THE BROWN
CIRCLES IS KNOWN TO ACTIVATE
MICROGLIA AND WHEN IT DOES SO
WHAT HAPPENS IS AN INCREASE IN
TRANSCRIPTION FACTORS IN
MICROGLIA AND PROINFLAMMATORY
KINOKINES AND DECREASE IN GABA
RECEPTOR REGULATION AND WHAT YOU
HAVE AT THE END IS AN INCREASE
IN INFLAMMATION AND INCREASE IN
PAIN SENSITIVITY ALL FEATURES
THAT OCCUR WITH OPIOID INDUCED
HYPERALGESIA.
BECAUSE OF THE NOCICEPTION IN
PAIN THERE'S BEEN AN INCREASED
INTEREST IN INCREASING THE DRUG
AS ANY ANALGESIC TO TREAT PAIN
APART FROM THE USE AS AN
ANALGESIC AND THERE IS VERY
SIGNIFICANT VARIABILITY ON WHEN
TO USE IT AND WHAT INDICATION.
WHAT IT WILL BEST SERVE.
IT'S USED IN TREATING
INDIVIDUALS WITH ACUTE AND
CHRONIC PAIN AND OPIOID
INTOLERANT PATIENTS AND USED IN
MANY PLACES IN THE HOSPITAL AND
EMERGENCY DEPARTMENTS AND
OPERATING ROOMS AND WE USE IT
OFTEN.
ACUTE CARE AWARDS AND ICU OR
PATIENT FACILITIES.
BOTH WITH SINGLE DOSE AND
CONTINUED INFUSIONS AND DOSE
VARIES QUITE A BIT.
THE GUIDELINES BECAUSE OF THE
WIDE VARIABILITY ON THE USER OF
THE DRUG, THE AMERICAN SOCIETY
OF REGIONAL PAIN MEDICINE AND
THE ACADEMY OF PAIN MEDICINE AND
AMERICAN SOCIETY OF
ANESTHESIOLOGISTS CAME UP WITH
GUIDELINE FOR THE TREATMENT OF
ACUTE AND CHRONIC PAIN.
THE RECOMMENDATION AT THIS POINT
IS FOR PATIENTS UNDERGOING
PAINFUL SURGERY WHO ARE OPIOID
DEPENDENT OR TOLERANT AND
PATIENTS WITH SICKLE CELL PAIN
AND PEOPLE WITH SLEEP APNEA AND
THE DOSES RECOMMENDED HERE AND
THAT ACCEPTED DEFINITION IS LESS
THAN ONE MILLIGRAM PER KILO PER
HOUR AND ONE HAS TO TAKE INTO
ACCOUNT INDIVIDUAL RESPONSES AND
CAN BE USED AS A STAND ALONE
TREATMENT OR ADJUNCT OPIOID
BECAUSE OF IT'S SPARING
PROPERTIES.
THERE ARE CONTRAINDICATIONS FOR
THE USE OFF THE DRUG INCLUDING
CARDIOVASCULAR DISEASE AND
DYSFUNCTION AND PSYCHOSIS IN
PREGNANCY.
THERE'S WEAK EVIDENCE TO SUGGEST
ACUTE PAIN IN KETAMINE LESS SO.
NOW FOR CHRONIC PAIN AND THE
EVIDENCE IS WEEK FOR PATIENTS
WITH SPINAL CORD INJURY RELATED
PAIN.
AND WEAK EVIDENCE FOR SICKLE
CELL CHRONIC PAIN AND SEVERAL
NEURO PATHIC CONDITIONS.
THE EVIDENCE IS NOT CONVINCING.
TO THOSE RANGES FOR CHRONIC PAIN
ARE USUALLY HIGHER AND ONE
SHOULD TYPICALLY USE FOR LONGER
TIMES AND KEEP IN MIND
INDIVIDUAL RESPONSES THE
CONTRAINDICATIONS ARE SIMILAR.
THE NON-PARENTAL KETAMINE
FORMATIONS OR THE USE OF OTHER
MMDA RECEPTORS CAN BE USED FOR
FOLLOW-UP AND USE INTRANASAL FOR
PAIN.
IT SHOULD BE ADMINISTERED AS
RECOMMENDED AND IN PLACE WHERE'S
HEMODYNAMIC AND RESPIRATORY
MONITORING CAN TAKE PLACE
BECAUSE THE DRUG CAN HAVE
AFFECTS ON THOSE SYSTEMS.
AND DR. BRANDOW AND CURTIS
MENTIONED THE ASH GUIDELINES
FROM 2020.
I'M NOT GOING TO REPEAT THEM BUT
THEY ISSUED A RECOMMENDATION FOR
THE USE OF THE DRUG BECAUSE OF
THE LOW TO MODERATE CERTAINTY OF
THE EVIDENCE SUPPORTING ITS USE.
I'M GOING TO JUST GO THROUGH
THIS AND REMINDING THE DOSES
POINT TO THREE MILLIGRAMS TO
KILO NOT TO EXCEED THE DOSES AND
THE POTENTIAL HARMS I'LL TALK
ABOUT THIS LATER BUT THE
HALLUCINATIONS AND THERE'S A
RISK OF DIVERSION AND IT DOES
WARRANT PEOPLE WITH EXPERIENCE
WITH THE USE OF KETAMINE TO
ADMINISTER THE DRUG.
SO WHAT DOES THE EVIDENCE
SUPPORT IN THE USE OF KETAMINE
FOR SICKLE CELL PAIN?
IT'S SPARSE.
THERE'S TWO PUBLISHED RANDOMIZED
CLINICAL TRIALS AND MOST THE
EVIDENCE IS BASED ON BASE REPORT
AND COHORT STUDIES AND WE'LL GO
OVER A FEW OF THEM BUT THERE'S
SIGNIFICANT VARIABILITY WHICH
MAKES IT MORE CHALLENGING AND
USED IN EMERGENCY ROOMS AND ICUs
AND PATIENT WARDS.
FIRST THE RANDOMIZED CLINICAL
TRIALS.
TWO OF THEM ARE MENTIONED THAT
HAVE BEEN PUBLISHED.
THE FIRST IN CHILDREN TRYING TO
CONDUCT IN UGANDA.
HERE'S THE AGE GROUP ABOUT 12
YEARS OF AGE AND SO THE STUDY
WAS IN THE EMERGENCY ROOM
PATIENTS COME IN WITH SICKLE
CELL ACUTE PAIN AND THEY HAD TWO
COMPARISON GROUPS.
KETAMINE AND THOSE IN CHILDREN
RECEIVING 1 MILLIGRAM PER KILO
INTERVENIOUSLY AND THE COMPARE
TO ANOTHER GROUP AND THERE WERE
SIMILAR REDUCTIONS IN PAIN
SCORES BUT HOWEVER, THE TIME
BETWEEN ADMINISTRATION AND THE
MAXIMUM CHANGE IN PAIN SCORE
OCCURRED WHILE SHORTER IN
PATIENTS RECEIVING KETAMINE.
THEY DID SEEK QUITE A BIT OF
SIDE EFFECTS INCLUDING 15% OF
THE PATIENTS AND 11% HAD
DYSPHORIA AND SALIVIZATION AND
THE TREATMENT FAILURE WERE
HIGHER IN THE MORE TEEN --
MORPHINE TREATED GROUP.
THE SECOND TRIAL CONDUCTED IN
SAUDI ARABIA IN ADULTS THEY USED
A SMALLER DOSE .3 MILLIGRAMS PER
KILO AND MORE TEEN .1 PER KILO
AND FINDINGS SHOWED A SIMILAR
REDUCTION IN PAIN SCORE.
THOUGH THERE WAS SUGGESTION OF
OPIOIDS EFFECT FOR KETAMINE.
THIS IS ED, 120 MINUTES OF
OBSERVATION.
BECAUSE THERE'S A SMALLER DOSE
LIST INCIDENTS OF SIDE EFFECTS.
THE LARGE COHORT STUDIES IS MOST
WITH THE INFORMATION THERE'S
COHORT STUDIES.
ONE WAS DONE BY OUR GROUP AT THE
CHILDREN'S HOSPITAL IN D.C.
A SINGLE CENTER AND FOR PATIENTS
WITH ACUTE SICKLE CELL PAIN OVER
AN EIGHT-YEAR PERIOD NOT
INCLUDING PATIENTS WITH ACUTE
CHEST SYNDROME AND EXCLUDING
ADMINISTRATION OF KETAMINE THAT
WAS NOT MADE BY THE ACUTE PAIN.
SO STANDARDIZED SOMEWHAT.
THE INDICATIONS FOR THE USE OF
KETAMINE IN THE STUDY WERE
INADEQUATE ANALGESIA AND
PRESENCE OF UNDESIRABLE SIDE
EFFECTS AND OPIOID CONDITION.
WE HAD 85 PATIENTS AND SIMILAR
DISTRIBUTE USE OF MALES AND
FEMALES, CONCERN AND ADOLESCENTS
AND MEAN AGE OF 15 AND WHEN YOU
LOOK AT THE AND 20% WERE
ADMINISTERED TO CHILDREN BETWEEN
THE AGES OF 2 AND 11 AND 60%
BETWEEN THE AGES OF 12 AND 18
AND 20% FOR YOUNG ADULTS 19 TO
21.
THE NUMBER OF INFUSIONS FOR
PATIENTS IN OVER HALF THE
PATIENTS IN ABOUT 30% OR 15% OF
THE PATIENTS HAD OVER FIVE
INFUSIONS AND UP TO 11 AT A
TIME.
THE DURATION WENT FROM ONE DAY
TO SIX OR MORE DAYS.
AND THE DOSES ARE LISTED HERE.
THESE ARE THE DOSE FOR THE
CONTINUOUS INFUSION AND AT TIME
THE BOLUS OF ADMINISTRATION AND
REFLECT PRETTY MUCH WHAT YOU SEE
WHEN WE ADMIT SICKLE CELL
PATIENTS.
WHAT WE FOUND WAS A COHORT
STUDY.
THERE'S NO CONTROL GROUPS HERE.
SO WE DID SEE WHEN YOU COMPARE
THE LEVELS OF PAIN SCORE FROM
BEFORE KETAMINE WAS INITIATED
AND THE MEAN IN 95% CONFIDENCE
INTERVAL OF THE CHANGE.
SO A DROP IN 3 ON THE PAIN SCORE
AND THE SCALE THAT IS AND THERE
WAS ALSO A DECREASE IN OPIOID
INTAKE SHOWN HERE.
THIS IS MORPHINE EQUIVALENT.
THIS IS WHEN YOU LOOK AT THE
FIRST INDEPENDENT INFUSION FOR
EACH PATIENT AND WHEN YOU LOOK
AT OTHER INFUSIONS THE AFFECT IS
THE SAME AND DECREASE IN PAIN
SCORE AND WE LOOKED AT THE
PREDICTORS OF THE CHANGES IN
PAIN SCORING AND WE FOUND THAT
THIS IS A MULTIVARIATE ANALYSIS
MANY PATIENTS APPEARED TO HAVE
GREATER REDUCTION IN PAIN SCORE.
AND YOUNGER PATIENTS SIMILARLY
HAD GREATER REDUCTION IN PAIN
SCORE COMPARED TO OTHER PATIENTS
YOU CAN SEE HERE.
SO MALE IN YOUNGER PATIENTS WILL
HAVE GREATER INCREASE IN PAIN
SCORE.
THE PAIN LOCATION APPEARED TO
HAVE AN EFFECT IN THAT ABDOMINAL
PAIN.
THOSE ARE ASSOCIATED WITH
GREATER DECREASE IN PAIN SCORE
WITH THE USE OF KETAMINE.
GENOTYPE WAS ANOTHER FACTOR IN
THE MODEL AND NO AFFECT THERE.
NOW THE CHANGES IN OPIOID INTAKE
THE PREDICTORS ARE AGAIN AGE,
YOUNGER KIDS WILL HAVE A GREATER
REDUCTION IN MORPHINE IN OPIOID
USE AND WE SAW NO EFFECT OF SEX
IN THE PREDICTION AND A TREND TO
SUGGEST PATIENTS WITH SC DISEASE
WOULD HAVE LESSER DECREASE IN
OPIOID AND NO EFFECT IN PAIN
LOCATION.
WE ALSO LOOK AT WHEN YOU LOOK AT
THE ABSOLUTE DECREASE IN PAIN
SCORE IT DOESN'T MEAN ANYTHING.
WE LOOKED AT WHAT YIELDED WHAT
GROUP HAD THE MOST MEANINGFUL
CLINICAL REDUCTION.
FOR THIS STUDY WE DEFINED
CLINICALLY REDUCTION TO BE
GREATER THAN 20%.
THAT'S GOING TO BE SHOWN IN BLUE
IN LESS THAN 20% IN THIS BROWN
AREA.
GRAY I GUESS.
MALE PATIENTS HAD A GREATER
PROPORTION THAT YIELDED A
CLINICAL REDUCTION IN PAIN.
60% ADMINISTERED TO MALES WERE
COUPLED WITH CLINICAL MEANINGFUL
REDUCTION IN PAIN.
THOSE ADMINISTERED TO YOUNG
CHILDREN ABOUT 80% REACHED
CLINICALLY MEANINGFUL REDUCTION
AND PAIN LOCATED IN THE BACK
ABDOA --
BLACK MEN WITH MEANINGFUL PAIN
SCORED AND LESS RESPOND TO
KETAMINE AS RESPONDS TO OPIOID
INTAKE.
A GROUP IN
THE LOOKED AT THE EXPERIENCE
THEY LOOKED AT THIS AFTER OPIOID
DCA IN LOWER DOSES AND IN THREE
DAYS OF DURATION AND WHAT IS
REMARKABLE IS THEY DID SEE A
SIGNIFICANT INCIDENT OF SIDE
EFFECTS INCLUDING 22% TO SHORTEN
THE DURATION OR DISCONTINUATION
OF THE INFUSION OR REDUCTION OF
THE DOSE.
AND THEY FOUND DISASSOCIAAIIATE
FEELINGS AND AT DUKE THEY FOUND
AFTER THREE DAYS AND HERE IS THE
DISTRIBUTION.
AND 30 YEARS IS THE MEDIAN ABLE.
AND FOUND ONCE YOU START
INFUSION THERE'S A SIGNIFICANT
REDUCTION IN PAIN RATE FROM THE
BASELINE FROM THE STUDY SHOWING
ON THE Y AXIS YOU HAVE CHANGES
IN PAIN SCORES.
IN BLUE ARE THE DATA POINTS FOR
KETAMINE INFUSIONS THAT WERE
INITIATED EARLY IN THE
HOSPITALIZATION WITHIN THREE
DAYS AND IN THE YELLOW, THE
KETAMINE INFUSIONS STARTED THREE
DAYS AFTER INFUSION.
THOUGH THE PRIME POINTS YIELDED
NO DIFFERENCE WHEN YOU LOOK AT
REDUCTION IN PAIN SCORES IN DAY
ONE AND TWO AFTER OF INFUSION
YIELDED ABOUT SIGNIFICANT
REDUCTION IN PAIN SCORE ABOUT
25%.
VERSUS 2% WHEN STARTED EARLIER
AND 30% FROM DAY TWO BUT
INTERESTINGLY THE FINDINGS FROM
DAY THREE OF KETAMINE INFUSION
WERE NOT SUSTAINED.
THERE WAS NO CHANGE IN PAIN
SCORES.
AND UNLIKE OUR GROUP IN KIDS, IN
ADULTS THERE WERE NO ASSOCIATION
OF THE RESPONSE IN THE PATIENT
CHARACTERISTICS.
FOR PAIN IN SICKLE CELL THERE'S
LESS DATA, VERY LITTLE USED A
FEW TIMES WITHOUT ANY ANECDOTAL
CHANGES IN PAIN OR OPIOID INTAKE
AND KETAMINE IS AN ANALGESIC AND
USED WITH MORPHINE IN EMERGENCY
ROOM WITH SECOND HAICKLE CELL D
AND THERE MAY BE OPIOID SPARING
EFFECT HOWEVER, YOU DO SEE MORE
I'D EFFECTS WHEN KETAMINE IS
USED AND IT'S AN ADJUVANT TO
OPIOID WITHOUT RANDOMIZED TRIALS
THE DATA SUGGESTS THERE'S
SIGNIFICANT OPIOID INTAKE AND
THE EFFECT OF KETAMINE VARIES
ACCORDING TO SEX, AGE, PAIN
LOCATION, GENOTYPE.
THE TIMING IT APPEARS IT'S
KETAMINE WHEN STARTED EARLIER
AND WHEN HAVE YOU PAIN DECREASED
SIDE EFFECTS AND SUSPICION OF
OPIOID INDUCED HYPERALGESIA
THERE MAY BE A GOOD INDICATION
FOR ITS USE.
AND WHEN TO START SOME
SUGGESTIONS EARLY INITIATION MAY
BE BENEFICIAL.
THE DRUG IMPROVE PAIN CONTROL
AND HAS OPIOID AFFECTS BASED ON
THE EVIDENCE I CITED BUT
DEFINITIVE EVIDENCE IS LACKING
BUT AND CAN HAVE UNDESIRABLE
AFFECTS AND RISKS.
ONE THING THAT IS INTERESTING
AND I'LL ASK BEFORE CARROLL WHAT
HE THINK IT REMAINS UNKNOWN WHEN
THE ANTIDEPRESSANT EFFECT PLAYS
A ROLE AND WHERE IT CAN BE
ADMINISTERED SAFELY AND HAVE THE
BUILT TO MONITOR KETAMINE
APPEARS TO BE A REASONABLE AND
USEFUL OPTION TO TREAT PATIENTS
WITH SICKLE CELL DISEASE.
THIS IS MY GROUP.
THANK YOU AND MY COLLABORATORS
AND THANK YOU FOR YOUR
ATTENTION.
>> I WANTED TO SHARE OUR
EXPERIENCE.
I DON'T KNOW IF YOU KNOW
DR. CARULO ALSO INTERESTED IN
SICKLE CELL CARE.
WE WORKED TOGETHER A LONG TIME
AND PUT IN PLACE A CLINICAL
PRACTICE GUIDELINE WHERE WE USED
VERY LOW DOSES OF METHADONE
MAXING OUT AVERAGE BETWEEN 2.5
TO 7 MILLIGRAMS PER DAY FOR
THREE DAYS AND SHOWED A ROBUST
DECREASE IN OPIOID USE AND OTHER
ADVERSE EFFECTS OF OPIOID AND
THE RATIONALE WAS TO USE FOR
ACUTE PAIN MANAGEMENT AND DIDN'T
HAVE TO DEAL WITH USING AN IV
INFUSION AND WONDERED WHAT YOUR
THOUGHTS WERE ABOUT THAT AS AN
ALTERNATIVE TO KETAMINE.
>> I THINK IT'S A FANTASTIC
APPROACH.
WE USE IT A LOT IN THE OPERATING
ROOM AS AN ANALGESIC AND IN THE
SETTING I TALKED TO VERONICA
ABOUT THAT IT'S FANTASTIC.
I ENDORSE IT.
>> A RANDOMIZED TRIAL MAYBE IN
OUR FUTURE.
>> THANK YOU.
YOU MENTIONED A COUPLE
CONTRAINDICATIONS WITH
CARDIOVASCULAR DISEASE AND I
HOPE YOU CAN COMMENT ABOUT THOSE
IN OUR SICKLE CELL POPULATION
PARTICULARLY.
>> YOU CAN SEE HYPERTENSION,
TACHYCARDIA EVEN WORSE IN THE
SETTING OF ANEMIA THE PATIENTS
DON'T TOLERATE THAT.
AND A DRUG WITH A RELATIVE
INDICATION AND IF YOU HAVE A
PATIENT THAT'S HYPERTENSIVE AND
YOU HAVE IT TREATED IT'S NOT
OBSOLETE.
WHAT DO YOU THINK ABOUT AS AN
ANTIDEPRESSANT?
MY QUESTION ABOUT KETAMINE IS
USUALLY IS THIS A MAGIC SHOT OR
MAGIC RIFLE?
I'VE HAD MANY PEOPLE WITH
OPINIONS ABOUT METHADONE AND
SHOULD WE PUT EVERYONE ON DEXO
ME
METHOPHINE.
>> NOW I WILL INTRODUCE
DR. CARROLL AN INTERNATIONALLY
RECOGNIZED EXPERT IN THE
MULTI-DISCIPLINARY MANAGEMENT OF
COMPLEX AND HIGH-UTILIZING
PATIENTS WITH SICKLE CELL
DISEASE AND COMPLETED THE
GRADUATE MEDICAL TRAINING IN
ST. LOUIS.
HE COMPLETE D
>> SO I'M GOING TO TRY NOT TO
KEEP YOU FROM LUNCH.
I'M GOING TO TALK TO YOU ABOUT
HOW WE USE BUPRENORPHINE AND WE
USE IT AT HOPKINS FOR A COUPLE
THINGS THAT SOMETIMES OVERLAP
AND PROBABLY OVERLAP LESS THAN
YOU THINK WHICH IS PEOPLE WHO
ARE ON CHRONIC PAIN OPIOID
THERAPY OFTEN AT HIGH DOSES
AREN'T DOING VERY WELL WITH IT
A
AND PEOPLE IN THE HOSPITAL A LOT
OR HAVE ACUTE CHRONIC PAIN OR
HAVING TROUBLE STABILIZING THE
OPIOID DOSE IN CHRONIC
OUTPATIENT DACARE FOR UTILIZATI.
IT'S NOT MANY PEOPLE.
THIS IS LOOKING AT OUT PATIENT
FOR A YEAR AND OUR CLINICAL
LOOKING AT PRETTY MUCH THE SAME
THING WHICH IS TWO-THIRDS TAKE
LESS THAN A PILL A DAY BECAUSE
OF THE WAY THE SKEW WORKS BUT
SOME PEOPLE TAKE A GOOD AMOUNT
OF OPIOID AS AN OUT PATIENT.
IT'S ALL BEND HERE.
THIS IS WHAT IT LOOKS LIKE IN
OUR CLINIC.
THIS IS PROBABLY AN OVER
ESTIMATION.
BUT WE DO SEE THERE'S SOME
PEOPLE WHO TAKE HIGH DOSES OF
OPIOIDS.
THE OTHER THING IS I THINK THIS
THING ABOUT FREQUENCY
UTILIZATION AND ACUTE CARE AND
ACUTE PAIN AND OUT-PATIENT
OPIOID USE ARE PROBABLY LESS
RELATED THAN WE THINK THEY ARE.
THIS IS FROM A STUDY FROM A
COLLEGIATE HOPKINS LOOKING AT
THIS DATA ON ONE AXIS AND
FREQUENCY OF ACUTE CARE VISITS
ON THE OTHER AXIS.
IF YOU DO JUST A STRAIGHT
CORRELATION BETWEEN THE TWO IT'S
A WEAK TO POSITIVE BUT IF YOU
SPLINE IT AT ONE PILL A DAY OR
LESS YOU SEE ALL THE
RELATIONSHIP ON THE LOW END.
PEOPLE AVERAGING A PILL A DAY OF
OPIOIDS ROUGHLY THE RELATIONSHIP
BETWEEN HOW MUCH OPIOID THEY
TAKE AND HOW MUCH THEY'RE IN THE
HOSPITAL IN THE ED OR INFUSION
CENTER IS BASICALLY NIL.
THIS COULD BE TRUE OF THE WORLD
OR JUST US.
LIKE I SAID, WE PAY CLOSE
ATTENTION TO THIS THING ABOUT
PEOPLE IN THE HOSPITAL A LOT OR
ARE ON LOTS OF OPIOIDS AND
HAVING A LOT OF PAIN AND SOME
WIND UP ON BUPRENORPHINE AND THE
REASON THERE'S NOT MUCH OF A
CORRELATION IS BECAUSE THE UPPER
QUADRANT IS EMPTY.
PEOPLE EXCLUDE FROM THE STUDIO
-- STUDY MAYBE THEY AREN'T JUST
LOOKED AT AND I'D BE INTERESTED
IF THIS IS IN OUR WORLD OR BACK
YARD.
THIS IS ABOUT USING
BUPRENORPHINE FOR THESE GROUPS
OF PEOPLE FOR THAT REASON.
THAT BEING SAID, SO I AM PATH
LOGICALLY SIMPLE MINDED AS MANY
PEOPLE IN THE ROOM CAN ATTEST
TO.
I LIKE TO MAKE THINGS I CAN
UNDERSTAND.
I THINK BUPRENORPHINE ABOUT 80%
OF WHAT YOU NEED TO KNOW ABOUT
THE PHARMACOLOGY IS WHAT IT DOES
AT ONE RECEPTOR AND NEED TO KNOW
TWO THINGS ABOUT IT.
THE OPIOID RECEPTOR AND THE
RESPIRATORY SUPPRESSION AND
ANALGESIA AND ABOUT ALL OF IT.
TWO THINGS ARE FUNNY ABOUT IT.
ONE IS IT'S A PARTIAL AGONIST.
THAT MEANS THERE COMES A POINT
WHERE YOU GIVE MORE
BUPRENORPHINE AND YOU STEADILY
GIVE MORE AND IT CEILINGS OUT
AND IT KEEPS OCCUPYING THE
RECEPTOR AND THING 1.
THING 2 IS IT STICKS TO
RECEPTORS LIKE
>>YGLUE SO WHEN IT'S
ON THERE IT DOESN'T COME OFF
EASY AND SOME USEFUL AND SOME
COMPLICATING.
THE MAIN USEFUL THING ABOUT IT
IS THE CAUSE OF THE AFFECT IF
YOU'RE TOLERANT TO A SOLID DOSE
OF OPIOID OR BUPRENORPHINE AND
YOU TAKE MORE YOU WIND UP HAVING
EFFECT CEILING OUT BEFORE THE
RESPIRATORY SUPPRESSION KICKS IN
AND IT'S SAFER IN TERMS OF NOT
HAVING AN OVERDOSES.
IT'S ONE OF THE REASONS IT'S
USED IN ADDICTION TREATMENT.
THE OTHER THING THAT'S
COMPLICATED AND YOU HAVE AN
AGONIST AND SOMEONE WITH HIGH
TOLERANCE THE BUPRENORPHINE WILL
OUT COMPETE IT AND CAUSE
PRECIPITATED WITHDRAWAL NOT AS
BAD AS A FULL ANTAGONIST BUT
WHEN YOU TRANSITION PEOPLE FROM
AGONIST TO BUPRENORPHINE IT CAN
TAKE TECHNIQUE.
THERE'S A COUPLE WAYS TO DO IT.
WE DO IT BOTH WAYS AT HOPKINS.
I DON'T GOT 20 MINUTES AND WON'T
GO DETAILS BUT IF YOU WANT TO
TALK ABOUT IT LATER, I'LL BE
BACK THERE.
MY E-MAIL ADDRESS IS UP THERE.
SOME NICE THINGS ABOUT IT IS IT
HAS MODEST WITHDRAWAL AND IT
DOES ACT AS AN ANALGESIC AND HAS
INTRINSIC AGONIST ACTIVITY.
IT WAS FIRST APPROVED FOR THE
USE IN PAIN FOR THE PARENT
VERSION FIRST APPROVED FOR PAIN
PROBABLY LATE 80s, EARLY '90s
AND ADDICTION TREATMENT AND
OTHERS AND LOTS OF INJECTABLES
AND LONG ACTINGS AND HAD TWO OR
THREE COME ONLINE FOR
INDICATIONS FOR CHRONIC PAIN
WHICH IS PROBABLY OTHERS COMING
SOON.
AND IT'S A FUNNY OPIOID.
IT REQUIRES TECHNIQUE AND HAS
ADVANTAGES.
ONE THING I SHOULD POINT OUT
ABOUT THE WHOLE SAFETY THING AS
IT SAFER IN TERMS OF OVERDOSE IF
YOU'RE TOLERANT TO OPIOIDS.
IF YOU HAVE SOMEONE NOT TOLERANT
TO OPIOIDS AND GIVE THEM A BOAT
LOAD OF BUPRENORPHINE YOU CAN
OVERDOSE AND CAN DIE AND IT'S
PRETTY DANGEROUS BECAUSE THE
RECEPTOR IDENTITY MAKES IT HARD
TO REVERSE WITH AN ANTAGONIST.
IT'S NOT LIKE YOU CAN THROW IT
AT ANYBODY AND IT WILL BE SAFER.
YOU HAVE TO KNOW WHAT YOU'RE
DOING.
IT'S BEEN STUDIED IN SICKLE CELL
DISEASE AND THERE'S BEEN A FEW
CASE STUDIES AND BOTH MAINLY
LOOKED AT ACUTE CARE UTILIZATION
AS AN OUTCOME.
SO OUR STUDY SIMILAR
DEMOGRAPHICS TO OUR OVER ALL
POPULATION IN THE CLINIC EXCEPT
PROBABLY MORE PEOPLE WITH SS AND
GENOTYPES I THINK AND TRANSITION
PEOPLE ON AVERAGE TO 160 MO
MORPHINE EQUIV LEAPTS A DAY.
-- EQUIVALENTS A DAY AND TAKE
THEM TO SOMETHING UNDER 100
MORPHINE EQUIVALENTS AND SOME WE
SWITCH OVER BY MICRODOSES AND WE
PUT ALL THOSE TOGETHER IN THE
STUDY.
THIS HERE IS A SLIDE THAT SHOWS
THE AMOUNT OF BUPRENORPHINE
PEOPLE WOUND UP ON RELATIVE TO
THE AMOUNT OF OPIOID THEY WERE
TAKING BEFORE.
AND THERE'S TWO LINES.
THE MATH -- MAGENTA IS PRE
TAPERING DOWN AND THE BLUE LINE
IS THE DOSE PEOPLE WERE TAKING
AT THE TIME THEY SWITCHED OVER
TO BUPRENORPHINE AND THEN THE Y
AXIS IS SABOXONE SUB LINGUAL
VERSIONS.
I'LL TELL YOU PART OF WHY THAT
IS IN A SECOND.
WHAT YOU'LL SEE IS THAT PEOPLE
WOUND UP BETWEEN LIKE 8 AND 16.
THEY HAD A FEW OUTLIERS TAKING
24 MILLIGRAMS A DAY OF
BUPRENORPHINE EQUIVALENTS.
AND I ALSO SAY THAT WE HAD FEW
HAVING VERY MUCH WITHDRAWAL AND
MOST OF WHAT THE WITHDRAWAL
PEOPLE HAD TO THE EXTENT THEY
HAD ANY HAD TO DO WITH THE DOSE
THEY WERE TAPERING DOWN TO AND
THE LOWER PEOPLE'S TOLERANCES
THE EASIER AND I CAN TALK TO YOU
ABOUT THAT LATER.
YOU CAN E-MAIL ME.
THE LINES ON THE GRAPH ARE THE
TWO MORE RECENTLY APPROVED
CHRONIC PAIN PREPARATIONS OF
BUPRENORPHINE.
IF YOU READ THEIR PACKAGE
INSERTS THEY DON'T THINK MUCH
ABOUT TRANSITIONS PEOPLE OVER ON
HIGH DOSES OF OPIOIDS.
SO RIGHT HERE IS WHAT THE
PACKAGE INSERT IS IMPLIED THE
MAXIMUM DOSE TO SWITCH PEOPLE
OVER.
HERE IS THE OTHER.
THEY HAVE WAY LESS IN THEM.
SO 2 MILLIGRAMS OF SUBOXONE AND
THE LOWEST DOSE YOU CAN GET IS
SOMETHING LIKE 75 MICROGRAMS IV
ALL DAY.
SO AND A LOT OF OUR FOLKS WIND
UP ON 16 MILLIGRAMS OF SUBOXONE
AND THEY'RE NOT FIT
TRANSITIONING PEOPLE FROM HIGH
DOSES.
THE MAIN OUTCOME WAS ACUTE CARE
UTILIZATION AND YOU SEE IT
DROPPED.
ON AVERAGE IT DROPPED BY ABOUT
THREE-QUARTERS.
THE THING LESS IMPRESSIVE THAN
IT SOUNDS IS THE POST
DISTRIBUTION IS NOT LOW
UTILIZING PEOPLE SICKLE CELL
DISEASE.
YOU'LL SEE FIVISH ACUTE CARE
VISITS PER SIX MONTHS.
AND SO I SHOULD EMPHASIZE THESE
FOLKS ARE SICK.
THEY HAVE CHRONIC PAIN.
THEY OFTEN HAVE FREQUENT ACUTE
PAIN AND PSYCHIATRIC MORBIDITIES
AND ETCETERA, ETCETERA.
WHICH IS TO SAY THERE'S NO
MIRACLE TO BE HAD HERE.
IT'S A USEFUL TOOL BUT WON'T FIX
EVERY PROBLEM.
THE OTHER THING THAT GOES
AGAINST THAT IS THERE'S A FAIR
NUMBER OF PEOPLE TRANSITIONED
THAT WERE NOT PARTICULARLY
FREQUENT VISITORS BEFORE THEY
TRANSITIONED OVER AND PEOPLE
GOING TO HIGH DOSES AND MORE
TEEN EQUIVALENTS AND FOR SOME
FOLKS THERE WASN'T A LOT OF
UTILIZATION TO REDUCE AND TO THE
EXTENT THERE WERE PEOPLE WHO HAD
HIGH UTILIZATION AND DROPPED OFF
IT'S KIND OF IMPRESSIVE AT THE
SAME TIME THE OVER ALL
POPULATION ARE STILL SICK FOLKS.
THIS IS NOT PEER REVIEWED.
IT'S A COMPLETE PACK OF LIES.
DON'T BELIEVE A WORD I SAY BUT
I'LL TELL YOU ANY WAY.
IT'S DC.
I WANTED TO LOOK AT WHAT
HAPPENED TO THE PEOPLE WHO DID
COME IN TO THE INFUSION CENTER
IN THE ED IN THE HOSPITAL AND SO
ON BECAUSE BUPRENORPHINE
COMPLICATE D -- COMPLICATES WH
WE USUALLY USE AND WE GET FANCY
AND SOMETIMES REDUCE PEOPLE'S
STANDING BUPRENORPHINE DOSE WHEN
THEY COME IN FOR ACUTE CARE.
WE OFTEN USE KETAMINE AND RELY
ON NSAIDS AND THE QUESTION IS
HAVE YOU IMPROVED ONE THING AND
MADE SOMETHING ELSE WORSE?
THE BEST OF MY ABILITY TO TELL
YOU IT HASN'T CROSSED PEER
REVIEW BUT WE DIDN'T MAKE IT
WORSE.
THESE ARE CO-EFFICIENTS AND
PEOPLE THAT WENT TO IN PATIENT
THEY SHOWED UP WITH THE SAME
LEVEL AND THE OPIOID USE WENT
DOWN AND THAT'S AN ARTIFACT
BECAUSE A LOT OF THESE FOLKS
WERE IN BUPRENORPHINE AND THAT'S
NOT IN THERE AND MORE KETAMINE
USE AND WE USED IT AND THE
SUPPLY RAN OUT SO WE RAN OUT OF
OUR CHANCE TO TRY AND PEOPLE
DIDN'T STAY LONGER.
THE ED WAS WEIRDER.
SO REMEMBER ALL THE VISITS
DROPPED OFF SO THEY REALLY
DROPPED OFF IN THE E.D.
SO MUCH DISPROPORTIONATE TO THE
IN PATIENT SO WE HAD LESS PAIN
IMPROVEMENT AND PEOPLE SHOWED UP
WITH LESS ACTUAL PAIN TO BEGIN
WITH SO IF YOU DO SUBTRACTING
THEY SEEM TO WIND UP AT ABOUT
THE SAME PLACE WHEN THEY LEAVE
AS BEFORE BUT THERE LESS OFTEN
SO I THINK IT'S STILL A WASH.
AND THERE WAS A STUDY OF OUR
FOLKS WHO TRANSITIONED TO
BUPRENORPHINE AND I THINK YOU
SHOULD READ THIS PAPER.
SEVERAL THINGS EMERGED AND THEY
TRANSITIONED TO BUPRENORPHINE
AND SOME DIDN'T STAY ON IT.
SOME THINGS EMERGED AND WHAT THE
WHOLE THING WAS MOTIVATED BY
FROM THE PATIENT SIDE WAS THEY
WEREN'T HAPPY WHERE THEIR LIFE
WERE GOING AND DIDN'T LIKE
OPIOIDS VERY MUCH BUT THERE WAS
THIS BALANCE BETWEEN THE FEAR OF
CHANGE AND SOMETHING MAYBE
GETTING WORSE AND THE HOPE MAYBE
SOMETHING WOULD GET BETTER AND
THEY TALKED A LOT ABOUT THE
IMPORTANCE OF THERAPEUTIC
RELATIONSHIP WITH OUR STAFF IN
TERMS OF MAKING THAT DECISION.
I THINK IT'S REALLY IMPORTANT.
IN TERMS OF THE PERSPECTIVE ON
THINGS PRE AND POST.
THERE WAS SOME STUFF WELL THIS
SEEMS LIKE IT'S BETTER AND SOME
STUFF THAT WAS EH, SAME STUFF,
MAYBE A LITTLE BIT DITCH --
DIFFERENT.
PEM PEOPLE TALKED ABOUT THE
ADVERSE EFFECTS OF THE MEDICINE
AND FELT MORE ENGAGED AND
PRESENT IN THE BUPRENORPHINE AND
LESS THING IN THEIR HEAD LIKE
YOU DIDN'T HAVE TO MAKE SURE IT
WAS IN THEIR PURSE AND ONE
COMMENT WAS IT'S LIKE A
BACKGROUND MEDICATION BUT THEY
POINTED OUT YOU STILL HAVE TO
TAKE SOMETHING EVERY DAY AND YOU
HAVE SIDE EFFECT AND THERE'S
STIGMA ASSOCIATED WITH OPIOID
USE AND BUPRENORPHINE AND PEOPLE
WHO SEE YOU'RE ON BUPRENORPHINE
THEY THINK THINGS ABOUT YOU
WHICH MAY MAY ALREADY THINK.
SOME OF OUR PATIENTS SAID
THERE'S STIGMA THERE BOTH WAYS
AND MAY KNOW WHAT TO DO TO TREAT
THE PAIN.
THE BUPRENORPHINE AND COMPLICATE
THE PAIN TREATMENT.
LIKE I SAID, I THINK THIS IS A
FASCINATING STUDY.
LIKE I SAID, I THINK
BUPRENORPHINE IS A USEFUL TOOL
BUT I WANT TO EMPHASIZE THE WAY
WE DO IT WE'VE MADE COMPLEX PAIN
MANAGEMENT A STUDY AND SO AS WE
STARTED USING IT DROPPED INTO AN
OVER ALL STRATEGY
SO I THINK IT'S A TOOL TO HELP
US KIND OF FINISH SOME JOBS, BUT
I DON'T THINK, FOR EXAMPLE, THAT
IF YOU HAVE SOMEONE WHO'S
EXTREMELY COMPLICATED IN THE
HOSPITAL A WHOLE LOT, YOU HAVE A
TERRIBLE THERAPEUTIC
RELATIONSHIP WITH AND YOUR
ENTIRE SYSTEM IS NOT GEARED TO
TREAT THEM, JUST PUTTING THEM ON
BUPRENORPHINE IS PROBABLY NOT
GOING TO HAVE ALL THAT
JUSTIFICATION ITSELF.
AND I'VE SEEN CASES WHERE THAT'S
GONE PRETTY BADLY.
SO JUST TO HAMMER IT HOME, IT'S
STILL AN OPIOID, A WEIRD OPIOID,
BUT IT'S AN OPIOID, NOT GOING TO
TREAT SICKLE CELL DISEASE IN AND
OF ITSELF.
CHRONIC PAIN IS HARD TO TREAT,
HARD TO TREAT FOR ANY KIND OF
MEDICINE, HARD TO TREAT WITH
BUPRENORPHINE, IT'S GOING TO
COMPLICATE YOUR MANAGEMENT OF
ACUTE PAIN SO YOU HAVE TO HAVE A
WAY OF DOING THAT AND YOU HAVE
TO HAVE THAT FIGURED OUT BEFORE
YOU TRANSITION THE PATIENT OVER,
AND IT DOESN'T CHANGE ANYTHING
ELSE, RIGHT?
YOU'RE STILL GOING TO HAVE THE
SAME THERAPEUTIC RELATIONSHIP
YOU HAVE WITH THE PATIENT, THE
PATIENT IS STILL GOING TO HAVE
THEIR IDEAS ABOUT HOW THEIR PAIN
SHOULD BE MANAGED AND HOW THE
SYSTEM SHOULD RESPOND TO THEM
AND SO FORTH.
NO MEDICINE IS GOING TO CHANGE
ANY OF THAT.
SO THAT'S MOSTLY WHAT I HAD TO
SAY, AND THAT'S ME.
THAT'S AN L AND THAT'S A 1, IF
YOU'RE HANDWRITING IT, BECAUSE
POOR CHRIS CARROLL IN ECONOMICS
AT HOPKINS IS GETTING MY MAIL,
IT'S DRIVING THE MAN CRAZY, SO
MAKE SURE YOU WRITE IT DOWN IF
YOU WANT TO TALK TO ME.
AND THAT'S WHAT I HAD TO SAY.
[APPLAUSE]
ANY QUESTIONS?
I DON'T SEE ANY IN THE CHAT.
LOOKS LIKE NO.
OKAY.
WELL, THEN I GUESS IT'S
LUNCHTIME.
>> IT IS.
SO WE'RE RUNNING A BIT LATE.
JUST A BIT OF HOUSEKEEPING, IS
THAT OKAY?
SO WE'LL TAKE ABOUT 45 MINUTES LUNCH BREAK
I'M MONICA FROM JAMAICA.
ANOTHER JAMAICAN.
S WAY REALLY PLEASED, JENNIFER,
TO SEE HOW MANY JAMAICANS ARE
HERE.
YOU REALIZE HOW MUCH JAMAICANS
ARE HERE?
NEIL IS JAY M JAMAICAN, ANDREW -
MOVING GEARS A LITTLE BIT, GOING
INTO AN AREA OF REPRODUCTIVE
HEALTH ISSUES IN SICKLE CELL
DISEASE.
OUR FIRST SPEAKER IS GOING TO BE
DR. LYDIA PECKER, WHO IS AN
ASSISTANT PROFESSOR OF MEDICINE
AT JOHNS HOPKINS UNIVERSITY.
SHE RECEIVED HER
UNDERGRADUATE DEGREE IN AFRICAN
STUDIES FROM BROWN AND HER M.D.
FROM THE UNIVERSITY OF
PENNSYLVANIA MEDICAL SCHOOL.
SHE ALSO HOLDS A MASTER'S IN
HEALTH SCIENCE FROM THE
BLOOMBERG SCHOOL OF PUBLIC
HEALTH.
DR. PECKER'S PRIMARY RESEARCH IS
FOCUSED ON REPRODUCTIVE HEALTH
IN GIRLS AND WOMEN WITH SICKLE
CELL DISEASE, WITH PARTICULAR
FOCUS ON INFERTILITY RISKS AND
PREGNANCY.
SHE'S A MEMBER OF THE AMERICAN
SOCIETY OF HEMATOLOGY MATERNAL
HEALTH COMMITTEE, FOUNDATION FOR
WOMEN AND GIRLS WITH DISORDERS
MEDICAL ADVISORY COMMITTEE AND A
CO-FOUNDER OF THE SICKLE CELL
REPRODUCTIVE EDUCATION
DIRECTIVE.
SO WELCOME, I'M LOOKING FORWARD
TO YOUR TALK, LYDIA.
>
>> IT'S KIND OF A TREAT TO BE UP
HERE BECAUSE I REMEMBER MY FIRST
MEETING, I GOT TO SIT WAY IN THE
BACK AT SICKLE CELL IN FOCUS.
I HAD NO IDEA WHAT WAS GOING ON
AND I SAT WITH ELLIOTT FACHINSKI
AND HE JUST MUTTERED TO ME ABOUT
THE WHOLE MEETING ABOUT
EVERYTHING THAT WAS WRONG.
WE MISS YOU, ELLIOTT.
AND IF YOU'RE NEW TO THIS
MEETING AND YOU'RE NOT SITTING
NEXT TO AN ORIGINAL GANGSTER OF
SICKLE CELL DISEASE, GO SIT NEXT
TO ONE SO THEY CAN MUTTER AT YOU
FOR THE REST OF THE MEETING.
IT'S A SPECIAL EXPERIENCE.
NONE OF THOSE ARE MY NAME.
WHO'S GOT A GOOD JOKE?
NO?
DR. CARROLL?
WHO HAS A QUESTION IN THE CHAT?
DR. QUINN, YOU KNOW ANY GOOD
JOKES?
DR. LEONARD?
WELL, I'M FROM THE JAMAICAN
COLONY OF BROOKLYN, SO IT'S
REALLY NICE TO BE TOGETHER WITH
OUR COLLEAGUES FROM JAMAICA AND
TO MEET ONE ANOTHER IN PERSON IN
BETHESDA.
AND I'M REALLY DELIGHTED TO TALK
TO YOU ABOUT REPRODUCTIVE
HEALTHCARE.
THESE ARE MY DISCLOSURES.
I DID SOME CONSULTING WORK FOR
GBT AND NOVA NORDISK.
BOYS AND MEN'S REPRODUCTIVE
HEALTH ISN'T REALLY MY AREA OF
EXPERTISE BUT I REALLY STRONGLY
BELIEVE THAT IT DESERVES EXPERTS
WHO ARE COMMITTED TO ENSURING
THAT BOYS AND MEN RECEIVE
INDIVIDUALIZED HIGH QUALITY AND
EVIDENCE-BASED SEXUAL AND
REPRODUCTIVE HEALTHCARE.
WHILE THAT'S NOT THE TOTAL FOCUS
OF THIS TALK, I JUST WANTED TO
MAKE THAT STATEMENT REALLY
CLEAR.
THE OTHER THING I WANTED TO DO
AND I START TODAY DO THIS BY
CONJUCONJURE -- REMEMBER WE STAN
THE SHOULDERS OF GIANTS WHEN WE
DO THIS WORK.
WHAT MAKES REPRODUCTIVE
HEALTHCARE A CONCERN IN THE
SICKLE CELL DISEASE CLINIC IS
EVERYTHING THAT'S COME BEFORE.
SO I JUST WANTED TO TAKE A
MINUTE, WE CAN ALL TAKE LIKE A
DEEP BREATH AND IT CAN BE HARD
BEING A SICKLE CELL DOCTOR, I
JUST WANTED TO REMARK UPON HOW
FAR WE'VE COME IN 40 YEARS.
AND YET IT INDICATE HOW FAR WE
HAVE TO GO, BUT I JUST WANTED TO
TAKE THAT DEAP BREATH TOGETHER.
ONE OF THE THINGS WE'VE ACHIEVED
UNIVERSAL SURVIVAL, DR. QUINN'S
PUBLICATION REALLY BENCHMARKED
BENCHMARKEDTHAT FOR US IN THE DS
COHORT.
OUR YOUNG PEOPLE ARE STARTING TO
MEET THEIR LIFE'S HOPES AND
GOALS, THEIR EDUCATIONAL GOALS,
THEIR PROFESSIONAL GOALS, THEIR
PERSONAL AND RELATIONAL GOALS,
AND WE ARE SEEING INCREASINGLY
THAT IF YOU HAVE ACCESS TO HIGH
QUALITY LIFESPAN SICKLE CELL
DISEASE CARE, FIRST THAT IT
ENABLES OTHER THINGS, LIKE
ACCESS TO SEXUAL AND
REPRODUCTIVE HEALTHCARE, BUT
ALSO THAT IT'S JUST THE FLOOR
FOR DOING EVERYTHING WE NEED TO
DO FOR PEOPLE WITH SICKLE CELL
DISEASE.
WE CONTINUE TO SEE EVIDENCE OF
HYDROXYUREA'S PROFOUND BENEFIT
ACROSS THE LIFESPAN, EVEN AS WE
KNOW THAT THIS TRANSFORMATIONAL
THERAPY INTRODUCES NEW CARE
COMPLEXITIES IN ADULTHOOD IN
PARTICULAR.
AND FINALLY, CURATIVE THERAPIES,
WHICH ARE UNIVERSAL INDICATION
FOR FERTILITY PRESERVATION AND
REALLY FORCE OUR HAND ON THE
DISCUSSIONS AROUND FERTILITY
PRESERVATION IN THE SICKLE CELL
CLINIC ARE INCREASINGLY
AVAILABLE TO OUR PATIENTS.
WHAT AN AMAZING THING.
THIS IS A REPRODUCTIVE LIFE
PLAN, AND I WANTED TO JUST POINT
OUT THAT REPRODUCTIVE LIFE
PLANNING SPANS THE PEDIATRIC AND
ADULT CARE CONTEXTS, SO A LOT OF
WHAT WE'RE GOING TO SAY IS NOT
EXACTLY WHOLLY THE
RESPONSIBILITY OF PEDIATRICIANS
NOR WHOLLY THE RESPONSIBILITY OF
ADULT CARE PROVIDERS, AND THAT
THIS MAKES THIS WORK PERHAPS
MORE COMPLEX IN SOME WAYS BUT
ALSO EXCITING BECAUSE IT
INTRODUCES DIVERSE PRER PERSPECS
ON POTENTIALLY THE SAME
PROBLEMS.
I'M GOING TO START WITH A CASE
OF A YOUNG MAN THAT I CARED FOR,
A 27-YEAR-OLD WITH HEMOGLOBIN SS
WHO RECENTLY MOVED FROM ATLANTA
TO BALTIMORE WITH HIS FIANCE AND
HE'S TAKEN HYDROXYUREA FOR 10
YEARS AND MERCIFULLY FOR HIM
DOES NOT ROOT FOR THE ORIOLES.
THEY ARE PLANNING TO START THEIR
FAMILY AND HE WANTS TO KNOW WHAT
ANTICIPATORY GUIDANCE HE NEEDS,
WHAT HE SHOULD BE THINKING
ABOUT.
AND WHEN I TALK ABOUT
REPRODUCTIVE LIFE PLANNING AND
LIFESPANS IN PEOPLE WITH SICKLE
CELL DISEASE, I TEND TO PRESENT
IT LIKE THIS AS YOU SEE HERE,
WITH THIS KIND OF MORBID GRAPH
FROM HASSEL ET A.L. AL, THE LIFE
EXPECTANCY, AND WE PROVIDE
REPRODUCTIVE LIFE CARE TO A
GROUP OF PEOPLE WHO ARE RUNNING
OUT OF TIME BY THE TIME THEY'RE
20.
SO THERE'S ALL KINDS OF
URGENCIES THAT THAT PRESENTS,
AND ALSO ALL KINDS OF
COMPLEXITIES WHEN YOU THINK
ABOUT PLANNING, AND SO WE HAVE
TO HOLD THAT AT THE SAME TIME
THE URGENCY OF TREATING THIS
DISEASE AT THE SAME TIME
HONORING PEOPLE'S HOPES AND
DREAMS ABOUT THEIR FUTURE.
SO THE EFFECTS OF SICKLE CELL
DISEASE, I STRUCTURED THIS MALE
PART OF THE TALK TO REALLY BE
LIKE IF I WAS GOING TO DO MALE
STUFF, THESE ARE SOME OF THE
THINGS I WOULD START LOOKING
INTO BECAUSE WE DON'T HAVE A LOT
OF DATA ON ANY OF THIS.
SO IF YOU'RE INTERESTED IN THESE
QUESTIONS, MAYBE THESE ARE SOME
THINGS THAT WOULD BE OF CONCERN
TO.
BUT FOR MEN WITH SICKLE CELL
DISEASE, WE KNOW THERE'S
TESTICULAR DAMAGE, IT'S REALLY A
UNIVERSAL FEATURE OF THIS TEASE,
THE TESTICLES ARE AN END ORGAN.
IT LEADS TO HYPOGONADISM AND
SEMEN ABNORMALS IN MANY.
IASOSPERMIA TENDS TO BE
REVERSIBLE IN SOME CASES, WE
LACK REALLY ROBUST SYSTEMATIC
DATA AT THIS POINT.
THE EVIDENCE THAT EXISTS FROM
THE FRENCH IS REASSURING THAT
THE SPERMATOGONIAL POOL IS
UNAFFECTED IN PREPUBESCENT BOYS.
CURATIVE THERAPIES, HAPPILY YOU
CAN SHIELD THE TESTICLES UNLIKE
THE OVARIES FOR RADIATION.
SO ONE THING RAISED BY THE
EXISTING DATA IS A QUESTION I
HAD IS ARE WE MISSING DATA, ARE
WE MISSING PREGNANCIES IN OUR
YOUNG MEN WITH SICKLE CELL
DISEASE OR ARE WE MISSING
INFERTILITY?
THE FRENCH PUBLISHED LONG TERM
FOLLOW-UP DATA FROM THE HU
ESCORT COHORT, WHICH IS A COHORT
OF ADULTS AND CHILDREN WITH
SICKLE CELL DISEASE EXPOSED TO
HYDROXYUREA, AND IN THIS
PUBLICATION, 411 PATIENTS WERE
OVER 18 IN THIS COHORT AND
THEY'VE BEEN FOLLOWED FOR 4,000
PATIENT YEARS.
AND AMONG THOSE 411 ADULT MEN,
THEY ONLY IDENTIFIED 12
PREGNANTS IN PARTNERS OF
HU-TREATED MEN.
NOW, AGAIN, IS THIS MISSING DATA
WHICH THEY THEMSELVES SAY THEY
DIDN'T DEAL WITH IN THEIR STUDY?
IS THIS MISSING PREGNANCIES AND
IS THIS MISSING INFERTILITY?
WE DON'T KNOW.
IN THE SCDIC, THERE WERE
884 MALE PARTICIPANTS IN A STUDY
FROM PEDIATRIC BLOOD AND CANCER
PUBLISHED NOT LONG AGO, AND
AMONG MEN, THERE WAS A 16.9%
REPORT OF INFERTILITY THAT'S
HIGHER THAN AVERAGE FOR
UNAFFECTED MEP.
MEN.
AMONG THE 149 WHO REPORTED
INFERTILITY, ONLY 37 HAD BEEN TO
AN INFERTILITY SPECIALIST, AND
HAD SPERM ANALYSES PERFORMED AND
ABOUT HALF OF THEM HAD SEMEN
ABNORMALITIES, CONSISTENT WITH
WHAT WE KNOW ABOUT THIS DISEASE.
NOW TO BE CLEAR, THE RISK
FACTORS FOR INFERTILITY IN THIS
PATIENT POPULATION ARE NOT JUST
SPERM QUALITY.
THERE'S ERECTILE DYSFUNCTION,
COMPLEX HOSPITALIZATIONS, ALL
KINDS OF SOCIAL CHALLENGES
ASSOCIATED WITH THIS DISEASE.
SO WE'RE NOT PINNING THIS ON
SPERM, BUT JUST TO SAY THERE'S
SEVERAL STUDIES NOW RAISING THE
POSSIBILITY THAT WE'RE SEEING
HIGHER RATES OF INFERTILITY IN
THIS POPULATION THAN HAVE BEEN
PREVIOUSLY DISCUSSED.
AND IN FRANCE, WHERE THEY HAVE
ALWAYS HAD A VERY CONSERVATIVE
APPROACH TO FERTILITY
PRESERVATION, THEIR APPROACH IS
TO OFFER ALL MEN TREATED WITH
HYDROXYUREA A HYDROXYUREA
HOLIDAY AND FERTILITY
PRESERVATION IN DEFERENCE TO THE
DRUG'S POTENTIAL SIDE EFFECTS.
IT WOULD BE GREAT TO HEAR MORE
FROM THE FRENCH ABOUT HOW THEY
NAVIGATE THESE PROTOCOLS.
NOW, I TRIED TO MAKE THIS
PICTURE OF WHAT IT'S LIKE TO SIT
WITH A YOUNG MAN IN CLINIC AND
TALK ABOUT HYDROXYUREA AND
PREGNANCY, LIKE A 27-YEAR-OLD
WHO'S COMING TO YOU PLANNING
PREGNANCY.
AND I GUESS THIS SORT OF STARTS
IN THE UPPER LEFT-HAND CORNER,
DO YOU HAVE A BASELINE SPERM
ANALYSIS AVAILABLE?
AND USUALLY THE ANSWER TO THAT
IS NO.
BECAUSE MOST PEOPLE HAVE NOT
BEEN SENT FOR A BASELINE SEMEN
ANALYSIS.
THEY'RE CUMBERSOME, THEY REQUIRE
MASTURBATING, THEY'RE
EMBARRASSING, FOR SOME PEOPLE
THEY HAVEN'T BEEN COMPLETELY
EXPLAINED, ET CETERA.
BUT EVEN IF THERE WAS, HOW DO WE
DEFINE THAT?
FOR A POPULATION OF PATIENTS WHO
ARE INCREASINGLY EXPOSED TO
HYDROXYUREA, STARTING AT BIRTH
INTO ADULTHOOD, WHAT IS THEIR
NORMAL OR BASELINE SEMEN
ANALYSIS?
OKAY, FINE, SO MAYBE I DON'T
HAVE A SEMEN ANALYSIS.
ARE YOU WILLING TO GET ONE FOR
ME?
WHEN IS THAT TEST INDICATED?
SHOULD WE BE GETTING IT AT
TRANSITION TO ADULT CARE AS PART
OF ROUTINE LABS?
SHOULD WE BE DOING IT ONCE
PATIENTS HAVE INFERTILITY OR
SHOULD WE BE DOING IT AT SOME
TIME POINT BEFORE THEN?
PATIENTS WHO ARE UNWILLING,
UNINTERESTED OR UNABLE TO GET
SEMEN ANALYSES, WHAT SHOULD WE
TELL THEM ABOUT PURSUING
CONCEPTION OR FERTILITY
PRESERVATION ON OR OFF
HYDROXYUREA?
SHOULD WE WAIT AND SEE WHAT
THEIR SEMEN ANALYSIS IS BEFORE
WE HOLD THE HYDROXYUREA?
I MEAN, IT'S LIKE -- IT'S
BAFFLING AND IT'S A LOT TO TALK
ABOUT, AND YOU KNOW, THIS IS
WHAT THIS CONVERSATION IS LIKE
IN MY CLINIC.
SO MOSTLY IT'S THREE, FOUR OR
FIVE CONVERSATIONS, NOT JUST
ONE.
BECAUSE MEN HAVE TO MAKE A
DECISION ABOUT A LOT OF
DIFFERENT TIME POINTS.
ANYWAY, THIS WOULD BE A PLACE
WHERE I WOULD START LOOKING IN
THE ADULT CLINIC IF I WAS
INTERESTED IN THIS PROBLEM OF
DEFINING WHAT NORMAL SEMEN
PARAMETERS ARE FOR THIS
POPULATION AND HOW WE SHOULD BE
PROVIDING THIS CLINICAL CARE.
I THINK IT'S A MUCH MORE
DIFFICULT CONVERSATION IN LATE
ADOLESCENCE AND IN PEDIATRIC
CARE.
DURING THIS ROUTINE REVIEW OF
SYSTEM WITH THIS NEW PATIENT, HE
REPORTS NO HISTORY OF PRIAPISM
BUT HE DOESN'T EVEN KNOW WHAT
THAT IS.
THIS HIGHLIGHTS THAT ON THE DATA
THAT EXISTS, THERE'S A HIGH
CONCERN THAT WE UNDERDETICKET IT
AND I THINK PART OF THAT MAY
JUST BE DUE TO LACK OF KNOWLEDGE
ABOUT WHAT THIS COMPLICATION IS.
IN ANY CASE, IT AFFECTS ABOUT
30% OF BOYS AND MEN WITH SICKLE
CELL DISEASE.
IT'S A RISK FACTOR FOR ERECTILE
DYSFUNCTION WHICH IS A RISK
FACTOR FOR INFERTILITY.
IT'S ALSO A RISK FACTOR FOR
TERRIBLE DEPRESSION, ANXIETY,
REALLY LOW QUALITY OF LIFE AND
WE DON'T TALK ABOUT IT THIS WAY
BUT I'VE BEEN REALLY IMPRESSED
OVER THE LAST FIVE YEARS TO
OBSERVE HOW DISRUPTED SLEEP IS
FOR THESE YOUNG MEN WHO HAVE
PRIAPISM.
THEY WAKE UP EVERY NIGHT, IT
WON'T GO AWAY, THEY GET UP, THEY
INSTIGATE A STEAL SYNDROME BY
GOING FOR A WALK AND THEY LEARN
ALL OF THESE TECHNIQUES TO
SELF-MANAGE BUT WHAT THEY CANNOT
MANAGE AWAY IS THE DISRUPTED
SLEEP AND OF COURSE THAT'S JUST
A CYCLE OF PAIN AND DEPRESSION
CONTRIBUTE FOR FOR SURE.
WE DON'T HAVE GREAT TREATMENTS
FOR THIS ALTHOUGH WE'RE ALL
HOLDING OUT HOPE FOR THE FACE
2 CRIZANLIZUMAB STUDY UNDERWAY
AND FOR WHICH HOPEFUL OUTCOMES
SO FAR HAVE BEEN REPORTED.
IT REQUIRES MULTIDISCIPLINARY --
WE NEED TO TEACH FAMILIES IT'S
AN EMERGENCY, PEOPLE NEED TO BE
SEEN FOR CARE IF THEY HAVE
PRIAPISM THAT LASTS MORE THAN
FOUR HOURS.
IT'S SO BAD I LIKE TO SAY IT
THIS WAY, IT'S AN INDICATION FOR
CURATIVE THERAPY.
MANY OF THE CURATIVE THERAPY
TRIALS HAVE PRIAPISM AS AN
INCLUSION CRITERIA.
SO IT'S A MARKER OF DISEASE
SEVERITY AND WE HAVE TO TREAT IT
THAT WAY.
THE SUN DOES NOT SHINE ON THIS
27-YEAR-OLD BECAUSE I SEND HIS
PARTNER FOR PARTNER TESTING AND
WHEN WE GET THE RESULTS BACK,
SHE HAS C TRAIT AND HER PARENTS
MAKE HER CALL OFF THE WEDDING.
WHICH LEADS ME TO MY FINAL POINT
ABOUT YOUNG MEN IN THE SICKLE
CELL DISEASE CLINIC WHICH IS
THAT I BELIEVE WE ARE MISSING
THE MENTAL HEALTH CARE NEEDS FOR
THIS PATIENT POPULATION.
IN THE UNITED STATES, 62% OF MEN
WHO IDENTIFY AS BLACK HAVE
EXPERIENCED TRAUMA, AND 40% OF
PEOPLE WITH SICKLE CELL DISEASE
IN GENERAL REPORT MENTAL
ILLNESS.
AS WE SCREEN FOR TRAUMATIC
EVENTS IN BALTIMORE FOR SURE,
WHICH IS A PRETTY VIOLENT CITY,
IT'S REALLY IMPRESSIVE HOW MANY
PEOPLE ARE ONE DEGREE OF
SEPARATION FROM EXTRAORDINARY
BODILY HARM.
YOU LAYER THAT ON TOP OF THE
SOCIAL EXPERIENCES OF LIFE WITH
SICKLE CELL DISEASE, WHICH ARE
THEMSELVES -- AFFECT ALL OF YOUR
SOCIAL RELATIONSHIPS, SO THESE
ARE PATIENTS WHO HAVE DELAYED
SEXUAL MATURITY, THEY HAVE A
HARD TIME MAKING FRIENDS IN
MIDDLE SCHOOL, THEY'RE BED
WETTERS, THEY'RE KIDS WHO
COULDN'T GO ON SLEEPOVERS
BECAUSE THEY WET THEIR BED AND
NOBODY EXPLAINED TO THEM IT
WASN'T THEIR FAULT IT WAS THEIR
SICKLE CELL DISEASE, AND THEY
HAVE ANXIETY ALTHOUGH THE BOYS
DON'T ALWAYS GET AS GOOD
TRAINING ABOUT TALKING ABOUT
THEIR FEELINGS ABOUT PASSING
THIS DISEASE ON TO THEIR
CHILDREN AND A LOT OF
MISUNDERSTANDING ABOUT HOW
SICKLE CELL DISEASE IS
INHERITED.
SO THERE'S BROAD NEED FOR
ENGAGEMENT OF OUR YOUNG MEN WITH
SICKLE CELL DISEASE.
AND THAT'S MY APPEAL TO ALL OF
YOU OUT THERE, TO CARE ABOUT THE
BOYS AND MEN WHO ARE COMING TO
MY CLINIC AND YOURS, BECAUSE I
THINK THEY REALLY NEED OUR CARE.
AND WITH THAT, I'M GOING TO
TRANSITION TO MY COMFORT ZONE
AND TALK A LITTLE BIT ABOUT
WOMEN'S REPRODUCTIVE HEL.
SO WE KNOW GIRLS AND WOMEN WITH
SICKLE CELL DISEASE FACE ANY
NUMBER OF COMPLICATIONS.
I'M GOING TO WALK YOU THROUGH A
REPRODUCTIVE LIFESPAN OF A
28-YEAR-OLD WITH HEMOGLOBIN SS
WHO WAS DIAGNOSED IN THE EARLY
1990s ON NEWBORN SCREENING,
AND HER BROTHER WAS CURED BY A
MATCH SIBLING DONOR TRANSPLANT.
HER ADOLESCENCE WAS INTERRUPTED
BY ACUTE CHEST, PAINFUL CRISES,
MENSTRUATION ASSOCIATED SICKLE
CELL PAIN, DAILY BACK PAIN AND
AVN.
IT WAS IN THAT CONTEXT THAT SHE
INITIATED BOTH HYDROXYUREA AND
HORMONAL CONTRACEPTIVE.
LET'S TALK A LITTLE BIT ABOUT
MENSTRUATION IN SICKLE CELL
DISEASE.
SO MANY GIRLS WITH SICKLE CELL
DISEASE START TO MENSTRUATE IN
THEIR MID TO LATE TEENAGE YEARS.
IT'S POSSIBLE THAT GENOTYPE
CONTRIBUTES TO THIS AND POSSIBLE
THAT TREATMENTS CHANGE THE
ONSET, THOUGH THAT'S VERY POORLY
DEFINED.
THIS IS A CONSTITUTIONAL DELAY
IN PUBERTY ONSET, SO THINGS THAT
CHANGE METABOLIC RATE LIKE
HYDROXYUREA AND CHRONIC
TRANSFUSIONS, IT'S PLAUSIBLE AT
LEAST THAT THEY MIGHT CHANGE THE
AGE AT PUBERTY.
THE ABSENCE OF PERIODS IN LATE
ADOLESCENCE IS NOT WELL
EXPLAINED BY SICKLE CELL
DISEASE.
IT SHOULD BE WORKED UP.
WE SHOULDN'T JUST LET OUR
COLLEAGUES ATTRIBUTE DELAYED
PUBERTY INTO THE LATE TEEN YEARS
AND EARLY 20s TO SICKLE CELL
DISEASE.
WE EXPECT REGULAR MEN STRAL
CYCLES, AND WE NEED TO TALK TO
OUR PATIENTS ABOUT THE KINDS OF
PAIN THEY EXPERIENCE WITH THEIR
MENSTRUATION AND PROVIDE SOME
ANTICIPATORY GUIDANCE THAT PAIN
IS NOT A CONSTANT ACROSS ONE'S
REPRODUCTIVE LIFESPAN, AND THAT
MENSTRUAL PAIN CAN ACTUALLY
START AS YOU GET OLDER SO
PERIODS THAT WERE ONCE NOT
PAINFUL MAY BECOME PAINFUL.
THIS IS LEO THE LATE BLOOMER WHO
I ALWAYS THINK OF WHEN I THINK
OF CHILDREN WITH SICKLE CELL
DISEASE AND IF YOU DON'T KNOW
THAT CHILDREN'S BOOK, IT'S A
GOOD ONE.
SO SICKLE PAIN IS ASSOCIATED
WITH MENSTRUATION, AND THIS IS
REALLY NICE WORK FROM MY
COLLEAGUE AND FRIEND DR. DEEVA
SHARMA.
HI, DEEVA, WE MISS YOU.
SHE IDENTIFIED IN A COHORT OF
WOMEN DOWN IN TENNESSEE THAT
THEY EXPLAINED THEIR EXPERIENCE
OF PAIN WITH MENSTRUATION EITHER
AS EXPERIENCING PERIOD PAIN
ONLY, 14% VASO-OCCLUSIVE SICKLE
PAIN AND 30% EXPERIENCE NEITHER.
TALKING TO WOMEN ABOUT THEIR
MENSTRUATION PAIN VERSUS THEIR
SICKLE PAIN IS ONE.
MOST FASCINATING THINGS THAT YOU
CAN DO IN THE CLINIC BECAUSE
IT'S LIKE ONE OF THESE PLACES
WHERE YOU HAVE THIS INSIGHT
ABOUT HOW SICKLE PAIN IS LIKE
JUST THIS CLEARLY DISTINCT
ENTITY FROM OTHER KINDS OF PAIN.
IN ANY CASE, WE KNOW THAT
THROMBOSIS RISK IN SICKLE CELL
IS AKIN TO OTHER HIGH RISK
THROMBOPHILIAS, AND WE KNOW THAT
IT'S PLAUSIBLE THAT
CONTRACEPTION COULD BE USED TO
AFFECT PAIN WITH PERIODS.
SO I JUST WANTED TO STRESS THAT
PROGESTIN ONLY CONTRACEPTION IS
FIRST LINE FOR SICKLE CELL
DISEASE AND I'LL TALK ABOUT THAT
IN A MOMENT.
THE OTHER THING THAT ISN'T WELL
ADDRESSED BY THE LITERATURE BUT
WE START TO SEE HINTS OF IT THAT
IT MIGHT BE EFFECTIVE IS IT'S
NEVER BEEN STUDIED WHETHER
COMBINATION THERAPY WITH
HYDROXYUREA AND CONTRASEPTION
MIGHT BE AN EFFECTIVE WAY TO
ADDRESS WOMEN WHO ARE REALLY
PROFOUNDLY AFFECTED BY MENSTRUAL
PAIN AND SICKLE CELL PAIN, AND
I'D REALLY LIKE TO ANSWER THAT
QUESTION SOMETIME IN THE FUTURE.
SO SHOULD WE BE THINKING OF THIS
AND DESCRIBING IT AS COMBINATION
THERAPY FOR OUR PATIENTS.
I'M NOT TRYING TO MAKE YOU GO
BLIND HERE, BUT RECENTLY WE WERE
AT THE CDC TALKING ABOUT THE
MEDICAL ELIGIBILITY CRITERIA FOR
CONTRACEPTION AND I JUST WANTED
TO WALK YOU THROUGH SOME OF THE
EVOLVING THINKING ABOUT
CONTRACEPTIVE USE FOR GIRLS AND
WOMEN WITH SICKLE CELL DISEASE.
SO JUST TO WALK YOU THROUGH THE
MEDICAL ELIGIBILITY CRITERIA FOR
CONTRACEPTION WHICH ARE THE CDC
GUIDELINES THAT BROADLY INFORM
CONTRACEPTION PRESCRIBING ACROSS
THE UNITED STATES, YOU CAN SEE
THERE'S A CONDITION,
SUBCONDITION AND THEN A NUMBER
OF DIFFERENT CONTRACEPTIVE
METHODS, COPPER IUD, HORMONAL
IUD, IMPLANT, DEPO,
PROGESTIN-ONLY PILLS AND THEN
THE COMBINED HORMONAL
CONTRACEPTION WHICH ARE
ESTROGEN-CONTAINING PILLS.
AND THERE'S A NUMBER OF
DIFFERENT OBSERVATIONS TO MAKE
HERE, BUT LET'S JUST FIND SICKLE
CELL.
IT'S A LITTLE HARD TO DO, ISN'T
IT?
IN THESE 2016 GUIDELINES, ALL
THE FORMS OF CONTRACEPTION WERE
GREEN LIGHTED FOR SICKLE CELL
DISEASE.
AND YET, PEOPLE WITH KNOWN
THROMBOGENIC MUTATIONS, WHICH
PEOPLE WITH SICKLE CELL DISEASE
BY VIRTU VIRTUE OF THEIR THROMBS
RISK, IT'S EQUIVALENT TO HT3 FOR
EXAMPLE.
IT WAS SUGGESTED THEY NOT
RECEIVE COMBINED HORMONAL
CONTRACEPTION.
I THINK THIS GETS EVEN MORE
INTERESTING AS YOU LOOK AT SOME
OF THESE OTHER CONDITIONS WHERE
CONTRACEPTION USE WAS SOMEHOW
RESTRICTED AND IDENTIFY THAT
MANY OF THESE THINGS HAPPEN TO
PEOPLE WITH SICKLE CELL DISEASE
AND YET THE GUIDELINE DOES NOT
CAPTURE ANY OF THIS NUANCE FOR
OUR PATIENT POPULATION, SO FOR
EXAMPLE, GALLBLADDER DISEASE,
NEAR UNIVERSAL FACTOR CHANGES
WHETHER YOU SHOULD BE PRESCRIBED
HORMONAL CONTRACEPTION.
ALL OF THESE ALSO HAVE A
RELATIVE CONTRAINDICATION TO
COMBINED HORMONAL CONTRACEPTION.
AND SO I WORRY THAT THE EXISTING
GUIDELINE DOES NOT HELP US THINK
WELL AND ESPECIALLY HELP PEOPLE
WITH SICKLE CELL DISEASE THINK
WELL ABOUT ALL THE DIFFERENT
KINDS OF COMPLICATIONS THAT
AFFECT OUR PATIENTS WE NEED TO
SCREEN FOR BEFORE WE PRESCRIBE
THEM CONTRACEPTION.
THERE'S ONE OTHER POINT I WANTED
TO MAKE ABOUT THIS GUIDELINE,
BECAUSE I THINK IT'S IMPORTANT
TO LEARN HOW TO READ WHAT BIG
POWERFUL INSTITUTIONS ARE DOING
WITH AND FOR SICKLE CELL DISEASE
WITH A KEEN EYE.
ONE OF THE THINGS THAT THIS
GUIDELINE DID IS IT BAKED
STRUCTURAL INEQUALITY INTO THE
CARE OF OUR PATIENTS.
AND THIS IS WHY WE NEED A SEAT
AT THE TABLE WHEN THE CDC MAKES
GUIDELINES LIKE THIS.
SO I'LL JUST POINT OUT, OUR
FRIEND CYSTIC FIBROSIS SOMEHOW
GOT MARKED AS A CONDITION AS
OPPOSED TO A SUBCONDITION, AND
WHAT YOU CAN SEE ON THIS LIST IS
THAT EVERYTHING THAT WAS LISTED
AS A CONDITION GETS NUANCE, IT
GETS POTENTIAL SUBCONDITIONS.
BUT SICKLE CELL DISEASE WAS
LISTED AS A SUBCONDITION, SO
IT'S IMPOSSIBLE TO BAKE IN
NUANCE INTO HOW WE CARE FOR
THESE PATIENTS INTO THE WAY THIS
GUIDELINE WAS WRITTEN.
AND SO IS IT THE BE ALL END ALL
HERE?
MAYBE NOT, BUT I THINK IT'S AN
IMPORTANT THING TO THINK ABOUT,
WHERE IS SICKLE CELL, WHY IS IT
BEING PUT IN A SUBCONDITION WHEN
SOME OF THESE OTHER DISEASES ARE
BEING PUT IN CONDITIONS.
THIS WAS A CRITIQUE THAT THE CDC
WAS OPEN TO, TO THEIR CREDIT.
SO COMING IN THE SPRING OF 2024,
YOU CAN EXPECT UPDATED GUIDANCE
ON SICKLE CELL DISEASE AND
HORMONAL CONTRACEPTION, AND
BECAUSE OF THE RECOGNIZED
THROMBOSIS RISKS ASSOCIATED WITH
THIS DISEASE, YOU CAN EXPECT
THAT THERE WILL BE MORE
RESTRICTIVE RECOMMENDATIONS FOR
COMBINED HORMONAL CONTRACEPTION
FOR THIS PATIENT POPULATION.
I DO NOT KNOW HOW THEY ARE GOING
TO RULE ON DEPO.
I THINK THIS IS A REALLY
CHALLENGING POINT.
THEY ARE MOVING TOWARDS
RESTRICTING DEPO ACCESS FOR
OTHER GROUPS OF HIGH RISK
THROMBOPHILIAS, AND YOU KNOW, WE
HAVE THIS ANCIENT DATA THAT DEPO
REDUCES PAIN IN WOMEN WITH
SICKLE CELL DISEASE AND SO WE
REALLY LIKE DEPO FOR THAT
REASON.
BUT ACTUALLY THE DATA PREDATES
HYDROXYUREA USE, SO I THINK WE
SHOULD REALLY NOT BE THINKING --
HANGING OUR HATS ON THAT DATA.
IN ANY CASE, PEOPLE LIKE ANDREA
ROWE AND ANDREA SPARKENBOUGH ARE
INTERESTED, SARAH O'BRIEN, AND
WE SHOULD REALLY BE WATCHING
THEM AND CHEERING THEM ON AS
THEY TRY TO HELP US FIGURE OUT
SOME OF THESE PUZZLES RELATED TO
CONTRACEPTION AND THROMBOSIS
BECAUSE WHILE IT'S NICE TO
STRATIFY FOR OTHER POPULATIONS
IDEALLY WE WOULD HAVE SPECIFIC
DATA FOR RISK AND HIGHLY
INDIVIDUALIZED CARE.
THIS IS A FANTASTIC STUDY FROM
NIGERIA THAT INVOLVED HUNDREDS
OF PEOPLE WITH SICKLE CELL
DISEASE, WOMEN WITH SICKLE CELL
DISEASE WHO ARE MARRIED AND A
COUPLE HUNDRED CONTROLS, AND IT
JUST HIGHLIGHTED WHAT THE GROUP
AT MOUNT SINAI IN NEW YORK HAD
ALREADY IDENTIFIED, WHICH IS
THAT WOMEN WITH SICKLE CELL
DISEASE ARE AT INCREASED RISK
FOR DISPARUNIA, ASSOCIATED WITH
CHRONIC PAIN.
IT'S NOT SOMETHING WE TALK ABOUT
BUT CERTAINLY A QUALITY OF LIFE
ISSUE.
AND I HOPE YOU CAN SEE IN THIS
GRAPH FROM NIGERIAN MARRIED
WOMEN THAT THE SEXUAL
SATISFACTION AND MARITAL
SATISFACTION SCORES ARE JUST
ABOUT HALF OF THOSE TO
UNAFFECTED WOMEN.
HOW DOES IT COMPARE TO PEOPLE
WITH OTHER COMPLEX CHRONIC
CONDITIONS? I DON'T KNOW.
BUT IT CAN BE INTRINSICALLY
VALUABLE TO US AS WE TAKE CARE
OF OUR PATIENTS.
OKAY.
SO SHE TOOK SOME HORMONAL
CONTRACEPTION, COMBINED HORMONAL
CONTRACEPTION WITHOUT EVENT.
SHE TOOK HER HYDROXYUREA REALLY
WELL.
SHE GOT MARRIED AND SHE ACTUALLY
DIDN'T HAVE MANY COMPLICATIONS
IN LATE ADD LE SEN LENS, SHE HAA
LITTLE BIT OF AVN FOR WHICH SHE
TAKES A LITTLE BIT OF TYLENOL
AND NSAIDS.
IN ANY CASE, SHE TOLD ME SHE
WANTS TO GET PREGNANT.
SO LET'S WALK THROUGH WHAT WE
THINKING ABOUT, THE WHEELS THAT
START TURNING WHEN YOU'RE
PROVIDING PRECONCEPTION CARE TO
WOMEN WITH SICKLE CELL DISEASE.
THERE'S A LOT OF PIECES, ONLY TO
SAY WE NEED TO THINK ABOUT
PARTNER TESTING, GENETIC
COUNSELING, WHAT DISEASE
MODIFYING THERAPIES WE'RE USING,
WHAT OTHER MEDICATIONS NEED TO
BE STARTED AND STOPPED.
INCREASINGLY I TALK TO WOMEN
ABOUT FERTILITY AND INFERTILITY
MOSTLY BECAUSE THEY'RE ALREADY
WORRIED ABOUT IT SO IF I DON'T
BRING IT UP THEY'RE ANXIOUS.
HOW DO WE KNOW IF YOU'RE FERTILE
OR INFERTILE?
WE KNOW YOUR INFERTILE FOR
TRYING FOR 6 OR 12 MONTHS,
DEPENDING ON HOW OLD YOU ARE.
SO WE START TO TALK ABOUT THESE
THINGS AS PEOPLE START TO PURSUE
PREGNANCY.
THIS PATIENT DIDN'T HAVE -- I
THINK IT'S IMPORTANT WE
ACKNOWLEDGE THE EXISTENCE OF
THIS 20-YEAR-OLD TECHNOLOGY AND
START TO THINK WITH WHAT DATA WE
HAVE TO INFORMITY USE.
WE KNOW THAT HAVING A CHILD WITH
SICKLE CELL DISEASE ALTERS THE
REPRODUCTIVE LIFE PLANS OF
PARENTS WHO HAVE THESE CHILDREN,
AND WE ALSO KNOW FROM STUDIES
FROM CHOP AND CHILDREN'S
NATIONAL AND HOPKINS THAT
PARENTS AND YOUNG ADULTS WITH
SICKLE CELL DISEASE ARE
INTERESTED IN LEARNING ABOUT
THIS TECHNOLOGY EVEN IF THEY
WOULD NOT CHOOSE IT FOR
THEMSELVES.
SO IT HIGHLIGHTS HOW COUNSELING
ABOUT TECHNOLOGIES, CURATIVE
THERAPIES, IN VITRO
FERTILIZATION, BECOMES A MARKER
OF QUALITY OF CARE AND ALSO
EQUAL QUALITY CARE.
IVF IS A HIGHLY SUCCESSFUL
TECHNOLOGY AND TH THE DATA FROME
UNITED KINGDOM IS IN 60 COUPLES,
I ALAS THIS IS THE BEST AMASSED
DATA WE HAVE ON THIS SUBJECT.
IT'S A TRICKY THING TO STUDY
BECAUSE THIS ISN'T A POPULATION
THAT HAS INFERTILITY.
THEY HAVE ANOTHER INDICATION FOR
THE USE OF IVF WITH THERAPIES.
IN ANY CASE, THE BRITISH WHO
PROVIDE COVERAGE OF IVF WITH PGT
WITH AN INDICATION TO AVOID
IMPLANTING AN EMBRYO AFFECTED BY
SICKLE CELL DISEASE REPORTED
OUTCOMES IN 60 COUPLES WITH
SICKLE TRAIT OR DISEASE
INCLUDING THREE WOMEN IN THEIR
EARLY 30s WITH SICKLE CELL
DISEASE WHO ALL CONCEIVED.
THEY REPORT A 63% TAKE-HOME BABY
RATE.
DOCTOR SAYING THAT IS LIKE THE
CUTEST BRITISH EUCH NISM I'VE
EVER HEARD, THE TAKE-HOME BABY
RATE.
IN ANY CASE THEY REPORT A 63%
TAKE-HOME BABY RATE.
I THINK WHAT'S SO INTRIGUING IS
IT'S NOT 63% BECAUSE THAT'S LIKE
THE BEST THEY COULD DO.
IT'S 63% BECAUSE PEOPLE DROPPED
OUT.
PEOPLE DROP OUT OF DOING IVF
BECAUSE IT'S UNBELIEVABLY
UNCERTAIN, IT'S UNBELIEVABLY
TAXING AND IT'S UNBELIEVABLY
STRESSFUL ON RELATIONSHIPS.
AND SO IF YOU HAVE FAMILIES OR
FRIENDS OR LOVED ONES WHO ARE
GOING THROUGH THIS EXPERIENCE,
YOU SHOULD KNOW THAT THE
UNCERTAINTY ASSOCIATED WITH THIS
PROCESS IS FANTASTIC, AND IT IS
REALLY HARD ON PEOPLE.
AND I THINK THAT THAT IS ALSO
RELEVANT WHEN WE START THINKING
ABOUT WHAT WE ARE DOING WITH
FERTILITY PRESERVATION FOR OUR
PATIENTS, AND SO THERE'S SOME
RUNNING TOGETHER OF THOSE IDEAS.
IN ANY CASE, THIS EXISTS.
AND WHAT WE LEARNED IS WE
STARTED TALKING ABOUT THIS AT
HOPKINS, WAS THAT THERE WAS NOT
ONE TOOL FOR PEOPLE AFFECTED BY
SICKLE CELL DISEASE OR TRAIT TO
DESCRIBE WHAT IVF WITH PGT WAS
THAT WAS DISEASE-SPECIFIC.
AND THAT EXISTING TOOLS WERE
WRITTEN AT THE 14TH TO 17TH
GRADE READING LEVEL.
NOTHING SAYS WHO A TECHNOLOGY IS
INTENDED FOR MORE THAN THAT, I
THINK.
IN ANY CASE, WE TRIED TO REPAIR
THAT PROBLEM.
THIS IS A FAMILY PLANNING
OPTIONS FOR PEOPLE WITH SICKLE
CELL TRAIT AND DISEASE DEVELOPED
AT HOPKINS AND IT MEETS U.S.
PATIENT EDUCATION HEALTH
LITERACY STANDARDS, AND IT WAS
DEEMED ACCEPTABLE, HOPEFUL AND
USEFUL BY OUR COMMUNITY PARTNERS
AND BY OUR PATIENTS AND IT'S
FREELY AVAILABLE ON THE SICKLE
CELL RED WEBSITE.
THE URL IS BELOW.
SO WE GIVE HER SOME INFORMATION
AND SHE SAYS WE MIGHT WANT TO
WAIT A COUPLE YEARS TO START OUR
FAMILY.
MAYBE NOT TODAY.
WHAT DO YOU THINK?
SHOULD I START TODAY?
I'M 28.
WELL, HERE'S WHAT IT'S LOOKING
LIKE.
SICKLE CELL DISEASE IS A DISEASE
OF ACCELERATED AGING.
IT MAKES SENSE THAT THIS WOULD
BE A DISEASE WITH A NARROW
FERTILE WINDOW.
YOU THINK ABOUT IT, MEN AR KEY
IS LATER AND WE SEE SOME EARLY
SIGNS THAT MENOPAUSE IS SOONER,
THAT SCRUNCHES IN YOUR
REPRODUCTIVE WINDOW.
JUST THAT ALONE BY LOGIC WOULD
DO IT.
SO THE CHALLENGE IS DO WE HAVE
GREAT CONTEMPORARY DATA?
WE DON'T.
BUT IN MENARCHE IN GIRLS WITH
SICKLE CELL DISEASE IT'S ABOUT
13, IN THE GENERAL POPULATION
IT'S CLOSER TO 11, AND
MENOPAUSE, THE LATE DR. SAMIR
BALLAS HELPED PUBLISH THE BEST
PAPER WE HAVE OF 15 BRAZILIAN
WOMEN WITH SS DISEASE AND THEIR
AGE AT MENOPAUSE, WHICH WAS
YOUNGER, 46 YEARS, AS OPPOSED TO
501 IN THE GENERAL BRAZILIAN
POPULATION.
IT'S IMPORTANT TO NOTE THAT THE
10 YEARS BEFORE MENOPAUSE ARE
ASSOCIATED WITH INFERTILITY
ONSET IN UNAFFECTED PEOPLE.
SO AGAIN, 46 YEARS, IF THAT'S
THE AGE AT ONSET OF MENOPAUSE,
YOU TAKE THAT BACK 10 YEARS AND
YOU'RE LOOKING AT AN AGE OF
INFERTILITY ONSET OF 35,
PROBABLY SOONER THAN THE GENERAL
POPULATION.
WE WERE INTERESTED IN THE
PROBLEM OF ANTIMA LAYERIAN
HORMONE, WHICH IS A MARKER OF
OVARIAN RESERVE THAT CAN BE
MEASURED ANY TIME IN THE
MENSTRUAL CYCLE.
WE WERE FORTUNATE TO RECEIVE
FUNDING FROM NHLBI TO HAVE A
LOOK AT THE SAMPLES FROM THE
CENTER OF HYDROXYUREA.
THIS INVOLVED ONLY WOMEN AND MEP
WITH SS DISEASE, NO BETA
THALASSEMIA IN THERE.
THERE WERE SAMPLES FROM
98 SUBJECTS FROM THAT STUDY.
UNFORTUNATELY THERE WERE ONLY
FOLLOW-UP SAMPLES AVAILABLE, SO
THERE WERE NO SAMPLES AVAILABLE
IN THE RANDOMIZED PART OF THE
STUDY TO START TO GET AT THIS
PROBLEM OF HYDROXYUREA IN THE
MOST ROBUST WAY.
BUT THIS IS WHAT WE FOUND, SO
AMH IS ON THE Y AXIS AND AH IS
ON THE X AXIS.
I HOPE THAT YOU CAN SEE THESE
BOXES WHICH ARE THE BOX PLOTS OF
THE AMHs FOR OUR STUDY
POPULATION.
THE BLACK BOXES ARE THE MH
LEVELS IN NORMATIVE CONTROL
DATA.
THE GREY BARS, I HOPE YOU AGREE,
ARE BELOW THE NORMATIVE BLACK
BARS, AND THEN YOU ALSO SEE THIS
DASHED LINE OF DIMINISHED
OVARIAN RESERVE, AND WOMEN WITH
SICKLE CELL DISEASE AT LEAST
SOME OF THEM ARE HAVING
DIMINISHED OVARIAN RESERVE AS
SOON AS AGE 20 OR 25.
AND SO WHAT ARE THE PLAUSIBLE
MECHANISMS OF OVARIAN INJURY IN
SICKLE CELL DISEASE?
DR. QUINN, THANK YOU FOR THIS
PICTURE.
THERE'S A COUPLE WAYS TO THINK
ABOUT OVARIAN INJURY IN SICKLE
CELL DISEASE, AND I'LL WALK YOU
THROUGH THIS.
SO SICKLE CELL DISEASE
PATHOPHYSIOLOGY BASICALLY
EVERYTHING THAT SICKLE CELL DOES
TO EVERY END ORGAN, OVARIES
DON'T LIKE THOSE THINGS EITHER,
SO THEY CAN BE CONCEPTUALIZED AS
AN END ORGAN IN SICKLE CELL
DISEASE AND THERE'S HEMOLYSIS,
ANEMIA, HYPOXIC ISCHEMIC INJURY,
ET CETERA.
WHETHER THAT LEADS TO
ACCELERATED DECLINE IN EGG
QUANTITY AND EGG QUALITY HAS NOT
BEEN ESTABLISHED, BUT THERE'S
QUESTIONS ABOUT HYDROXYUREA AND
CHRONIC TRANSFUSIONS.
THIS IS THE SUMMARY OF THE
EXISTING EPIDEMIOLOGY OF
HYDROXYUREA AND OVARIAN RESERVE,
POST PUBESCENT PEOPLE.
WE PUT TOGETHER DATA FROM
84 SUBJECT ACROSS THREE
SUBJECTS.
ALL HAD SICKLE CELL ANEMIA AND
WERE UNDER 30 YEARS OF AGE.
THERE WERE 27 SUBJECTS WITH
DIMINISHED OVARIAN RESERVE,
WHICH IS AN INDICATION FOR
FERTILITY PRESERVATION.
AND ONLY HYDROXYUREA-EXPOSED
SUBJECTS HAD DIMINISHED OVARIAN
RESERVE IN THIS SMALL COHORT.
THE NUMBER TO HARM IS 1.9 TO
4.8.
IN ONE OF OUR STUDIES THAT WE
DID AT HOPKINS, A HIGHER MCV WAS
ASSOCIATED WITH OVARIAN RESERVE.
IN FACT HYDROXYUREA TREATED
PATIENTS WHO DID NOT HAVE AN
ELEVATED MCV IS NOT HAVE
DIMINISHED OVARIAN RESERVE.
WE ALSO SEE SIGNS THAT MENOPAUSE
MAY OCCUR EARLIER IN PEOPLE
TREATED WITH HYDROXYUREA.
AGAIN VERY SMALL STUDY, AND AS
IS THE CASE IN ALL OF THESE
STUDIES, NOT YET POSSIBLE TO
TEASE OUT THE COMPLICATION OF
WHETHER THIS IS DISEASE SEVERITY
OR DRUG, ASSOCIATION NOT
CAUSATION STUDIES.
THANKS AGAIN, DR. QUINN.
SO WE ADOPTED DR. QUINN'S
EDITORIAL INTO A HASHTAG, AND
THE CENTRAL PREMISE ARGUMENT
THAT WE MADE USING OUR DATA WAS
THAT WE'RE SEEING DIMINISHED
OVARIAN RESERVE IN A FRACTION OF
YOUNG PEOPLE UNDER 30 YEARS OF
AGE WITH SICKLE CELL ANEMIA.
WE HAVE FERTILITY PRESERVATION
AS STANDARDS OF CARE FOR PEOPLE
WITH OVARIES IN THE FORM OF
OVARIAN TISSUE CRYOPRESERVATION
AND OOCYTE AND EMBRYO --
PRESERVATION.
WHAT WE SEE IN THE DATA IS THE
PEOPLE WE SHOULD BE HAVING THIS
CONVERSATION WITH, ALTHOUGH THE
TIMING AND CONTENT IS TO BE
DETERMINED, IS THAT THOSE FOR
WHOM HYDROXYUREA IS INDICATED
SHOULD HAVE THIS DISCUSSED WITH
THEM.
IN ADDITION, WHO ELSE ARE WE
THINKING ABOUT THIS?
SO WE'RE THINKING ABOUT
HYDROXYUREA, PEOPLE WITH AN
INDICATION TO TAKE HYDROXYUREA,
SO DISEASE SEVERITY AND/OR
CHILDREN WITH SS DISEASE.
THE OTHER GROUP OF PEOPLE THAT
WE'RE STARTING TO THINK ABOUT
FERTILITY PRESERVATION FOR ARE
PEOPLE WHO ARE POSTPONING CHILD
BEARING OR OTHERWISE HAVING
CHALLENGES AROUND CONCEPTION.
THE OTHER THING ABOUT THIS IS
THAT WE KNOW THAT OUR PATIENTS
SEEM TO HAVE INCREASED RISK FOR
INFERTILITY.
THE INFERTILITY RISK FACTORS ARE
BROAD.
WE GENERALLY SAY THAT YOU SHOULD
GIVE PEOPLE 12 MONTHS TO
CONCEIVE IF THEY'RE UNDER AGE 35
AND 6 MONTHS TO CONCEIVE IF
THEY'RE OVER AGE 35, BUT WHETHER
THOSE VALUES HOLD FOR OUR
PATIENT POPULATION IS ENTIRELY
UNCLEAR.
AND I'VE GIVEN ALL OF THE
BARRIERS AND CONSTRAINTS OUR
PATIENTS FACE GETTING TO
INFERTILITY SPECIALISTS.
I THINK IT'S WORTH STARTING THE
REFERRAL PROCESS EARLY SO THAT
OKAY, IF YOU DON'T NEED THEM,
YOU DON'T NEED THEM.
IN ANY CASE, THIS IS SOME OF THE
WORK AND SOME OF THE CHALLENGES
WE'VE BEEN THINKING ABOUT, ABOUT
FERTILITY PRESERVATION.
IT'S EASY TO FEEL DOOM AND GLOOM
ABOUT THIS STUFF BUT SOME OF THE
DATA LOOKS PRETTY NEAT.
THIS IS CHILDREN WITH SICKLE
CELL DISEASE, AND IF THIS IS
FROM DENMARK, THESE CHILDREN
WERE HEADED FOR CURATIVE
THERAPIES AND IT'S A COMPA COMPN
OF CHILDREN WITHOUT SICKLE OR
THALASSEMIA, THE RED TRIANGLES
ARE THAL AND THE BLUE DIAMOND
ARE SICKLE CELL DISEASE.
WHAT THEY'VE SHOWN IN THIS DATA,
AND IT SEEMS TO BE TRUE IN OTHER
COHORTS, ASH DATA PRESENTED BY
THE FRENCH LAST YEAR SORT OF
AFFIRMED THIS, IS THAT THE EGG
SUPPLY IN CHILDHOOD LOOKS PRETTY
GOOD, SO IT MAKES US WONDER,
SHOULD WE BE TRYING TO
UNDERSTAND MORE ABOUT OVARIAN
TISSUE CRYOPRESERVATION IN
CHILDREN AND DOING THAT UP
FRONT?
A SURGEON FROM DARTMOUTH A
COUPLE WEEKS AGO ASKED ME WHEN
HE WAS DO COLEY CYST STECT MES
ON THE PATIENTS IS IF HE SHOULD
TAKE A LITTLE OVARIAN TISSUE.
I THOUGHT IT WAS A LITTLE TOO
FAR IN THE FUTURE BUT I THINK
IT'S A QUESTION WORTH ASKING.
DR. MANWANI, BY THE LOOK ON YOUR
FACE I KNOW YOU'RE GETTING READY
TO ANSWER IT, THANK YOU.
SO IN ANY CASE, THE PROBLEM IS
LIKE WHAT DO WE DO?
WE PRESERVE TISSUE, WE PRESERVE
EMBRYOS, WE PRESERVE EGGS AND
THEN WE DON'T KNOW WHAT THE
OUTCOMES ARE AND THAT'S REALLY
TRUE, I CAN'T TELL YOU WHAT THE
OUTCOMES ARE WITH THESE
CRYOPRESERVED MATERIALS.
WE JUST DON'T HAVE THE DATA YET
AND WE DON'T HAVE THE SYSTEMS TO
COLLECT THE DATA PARTICULARLY
WELL.
WE'RE WORKING ON THAT.
FERTILITY PRESERVATION FOR OUR
PATIENT POPULATION IS I THINK
ONLY GOING TO INCREASE UNTIL DRN
HELP US FIND LESS TOXIC PREPTIVE
REGIMENS TO BRING CURE TO OUR
PATIENTS.
DR. TISDALE REASSURES ME THAT
THIS IS COMING.
BUT UNTIL THEN, FERTILITY
PRESERVATION IS GOING TO BE, I
THINK, AN INCREASING PART OF OUR
LANDSCAPE, AND I WANTED TO
STRESS THAT WE HAVE TO BE ABLE
TO DO THIS SAFELY FOR OUR
PATIENTS.
THIS IS OUR PROTOCOL AT HOPKINS
THAT WE USE WHEN WE'RE SENDING
PEOPLE THROUGH EGG HARVEST.
AND IT'S A PROTOCOL THAT WE RUN
IN CLOSE COLLABORATION WITH OUR
REPRODUCTIVE ENDOCRINOLOGISTS,
AND IT HELPED US IDENTIFY SOME
PITFALLS AND RISKS THAT MIGHT BE
UNIQUE TO PEOPLE WITH SICKLE
CELL DISEASE.
PARTICULARLY THERE'S AN EXPECTED
HYPERESTROGENEMIC STATE WITH
THIS PROCEDURE, SO THROMBOSIS
RISK MAY BE HIGH.
ANESTHESIOLOGISTS LOVE TO
GIVE -- WE TELL THEM DON'T DO
THAT WITH OUR PATIENTS.
AND PATIENTS MAY OR MAY NOT BE
AT INCREASED RISK FOR OVARIAN
HYPERSTIMULATION.
WHILE THE RISK IS GOING DOWN ALL
THE TIME IT'S A CAPILLARY LEAK
SYNDROME THAT CAN AFFECT THE
WHOLE BODY, BUT PARTICULARLY THE
LUNGS AND THE KIDNEYS AND THE GI
TRACT, SO IT CAN CAUSE PAIN AND
OTHER THINGS.
NOTHING THAT OUR PATIENTS LIKE.
WHEN MY PATIENTS GO FOR OVARIAN
HYPERSTIM I TELL THEM TO DO
DAILY WEIGHTS ON THEMSELVES FOR
ABOUT 5 TO 10 DAYS AFTER
PROCEDURE, BECAUSE MY THEORY,
WHICH IS TOTALLY THEORY, IS THAT
IF THEY ARE HAVING OVARIAN
HYPERSTIM AND IT'S A CAPILLARY
LEAK, THE FIRST THING I'LL SEE
IS THEIR WEIGHT WILL START TO GO
UP SO IT HELPS ME ANTICIPATE ANY
OWE TENSION PROBLEMS.
THE OTHER THING HERE IS THAT FOR
ALL OF OUR PATIENTS WITH SS OR S
BETA -- THALASSEMIA, WE TRY TO
GIVE THEM A HYDROXYUREA HOLIDAY.
HOW LONG, WE DON'T KNOW.
MAYBE ONE TO THREE MONTHS IF YOU
CAN, AND WE PUT THEM ON EXCHANGE
TRANSFUSIONS AND ALWAYS IF
THEY'RE NOT ON HYDROXYUREA OR
CHANGES TO BEGIN WITH, GIVE THEM
A TRANSFUSION JUST AS A
PREOPERATIVE PREPARATION FOR THE
STIM.
SOME HOPEFULNESS FROM OUR
COMMUNITY, WE NOWAK SES TO
FERTILITY PRESERVATION IS A
MASSIVE PROBLEM, AND I JUST
WANTED TO SHARE WITH YOU THAT BE
THE MATCH HAS PARTNERED WITH THE
SICKLE CELL REPRODUCTIVE HEALTH
DIRECTIVE AND IN THE LAST YEAR
HAS PROVIDED 16 GRANTS TO
PRESERVE FERTILITY FOR YOUNG
PEOPLE SECURING THERAPY FOR
PEOPLE WITH SICKLE CELL DISEASE.
YOU GUYS ARE REALLY DEAD OUT
THERE.
I KNOW YOU JUST HAD LUNCH.
THIS IS GREAT, YOU GUYS!
COME ON!
SO LISTEN, THIS IS REALLY
EXCITING, BE THE MATCH DIDN'T
REALIZE THERE WAS SUCH A NEED
FOR THIS, BUT ONCE THEY
RECOGNIZED THE NEED, THEY AGREED
TO CONTINUE THE PROGRAM FOR
ANOTHER YEAR, SO AS LONG AS OUR
COMMUNITY CONTINUES TO PURSUE
THIS FUNDING AND THERE ISN'T
MUCH PRIVATE FUNDING LIKE THIS
FOR INDIVIDUALS WITH SICKLE CELL
DISEASE, HOPEFULLY THE PROGRAM
WILL STAY ALIVE.
OKAY, WELL, EEN THE PLANNERS
SOMETIMES JUST DECIDE TO GET
PREGNANT, AND THAT IS WHAT
HAPPENED TO THIS YOUNG WOMAN.
SHE GOT PREGNANT, STOPPED HER
HYDROXYUREA, SHE CALLED ME UP
AND SHE SAID I HAVEN'T BEEN OFF
HYDROXYUREA SINCE I WAS A KID
AND I'M GETTING PAIN LIKE I'VE
NEVER HAD BEFORE, I JUST GOT OUT
OF THE HOSPITAL, WHAT SHOULD WE
DO NEXT?
WE ARE LIVING THROUGH A TOTALLY
STAGNANT TIME FOR PREGNANCY FOR
WOMEN WITH SICKLE CELL DISEASE,
AND I REALLY HOPE THAT IN THE
NEXT DECADE, WE CAN START TO
TURN THIS YACHT AROUND.
THESE ARE THREE PAPERS PUBLISHED
IN THE LAST 12 MONTHS, 24
MONTHS, ABOUT MATERNAL MORBIDITY
AND MORTALITY IN JAMAICA AND IN
THE UNITED STATES AND THEY ALL
DREW THE SAME CONCLUSION FROM
INDEPENDENT DATASETS, WHICH IS
THAT MATERNAL MORTALITY AND
MORBIDITY FOR GIRLS -- FOR WOMEN
WITH SICKLE CELL DISEASE IS
STAGNANT.
AND STRUCTURAL RACISM IS ALWAYS
PART OF THE PROBLEM FOR SICKLE
CELL DISEASE.
IN OUR ANALYSIS, STRUCTURAL AND
INTERPERSONAL RACISM MAY BE
ACCOUNTED FOR ABOUT 30% OF
SICKLE CELL DISEASE ASSOCIATED
SEVERE MATERNAL MORTALITY AND
MORBIDITY, AND A LOVELY PAPER
FROM OUR COLLEAGUES IN VIRGINIA
AND SOUTH CAROLINA AND FIVE U.S.
STATES, SICKLE CELL DISEASE
ACCOUNTED FOR .37% OF ABOUT A
MILLION PREGNANCIES IN PEOPLE
WHO IDENTIFY AS BLACK, BUT
ACCOUNTED FOR 6.9% OF THE SEVERE
MATERNAL MORBIDITY AND 8.9% OF
THE BLACK-WHITE SMM DISPARITY.
AND SO WE HAVE USED THIS TO
ARGUE THAT YOU CAN'T ACTUALLY
SOLVE THE RIDDLE OF MATERNAL
HEALTH DISPARITIES IN THIS
COUNTRY WITHOUT TAKING ON SICKLE
CELL DISEASE.
WE HAVE TO DO THIS TOGETHER WITH
OUR COLLEAGUES IN OB.
WELL, HOW BAD IS IT?
THIS IS FROM A RECENT ANALYSIS
OF THE NATIONAL INPATIENT
SAMPLE.
THESE ARE SEVERE MATERNAL
MORBIDITY INDEX, AND THE ONE
LINE IS PEOPLE WHO IDENTIFY AS
WHITE WHO ARE UNAFFECTED BY
SICKLE CELL DISEASE.
THE BLUE/PURPLE IS PEOPLE WHO
IDENTIFY AS BLACK, AND THE
ORANGE/YELLOW IS PEOPLE WHO
IDENTIFY AS BLACK AND HAVE
SICKLE CELL DISEASE.
AND OF COURSE ALL THESE PEOPLE
WERE PREGNANT.
SO I HOPE WHAT YOU CAN SEE IS
THAT THERE ARE FANTASTIC
INCREASED RISKS OF STROKES,
EMBOLI, ACUTE RESPIRATORY
DISTRESS SYNDROME, PULMONARY
EDEMA, THE NEED FOR VENTILATION,
SEPSIS, KIDNEY FAILURE, ET
CETERA.
THERE ARE ALSO CONCERNING
OUTCOMES FOR THE BABIES.
IUGR IS COMMON, PROBABLY RELATED
TO PLACENTAL ABNORMALITIES.
THE PLACENTA IS ALSO AN ENDORGAN
IN THIS DISEASE, AND FETAL
DEMISE IS ALSO MORE COMMON THAN
WE WOULD LIKE, PRETERM DELIVERY
TOO.
SO I WANTED TO TALK A LIT LITTLE
BIT ABOUT WHAT WE KNOW ABOUT
TRANSFUSIONS FOR THIS CONDITION
BECAUSE AT THE MOMENT, IT'S THE
ONLY THERAPY THAT DOESN'T HOLD A
TRYOGENIC RISK.
WE'LL TALK A LITTLE ABOUT
HYDROXYUREA BUT BLOOD
TRANSFUSIONS ARE REALLY THE
SAFEST THERAPY WE HAVE TO OFFER
WOMEN WITH SICKLE CELL DISEASE
IN PREGNANCY.
I WANTED TO TALK ABOUT THIS IN
THE CONTEXT OF HOW WE THINK
ABOUT THE STRENGTHS OF DIFFERENT
KINDS OF DATA BECAUSE THERE'S A
PAPER BY DR. KING AND
MALINOWSKI, I JUST WANTED TO
WALK YOU THROUGH THE RESULTS OF
THAT STUDY.
AMONG 12 STUDIES WITH 1200
PATIENTS, PROPHYLACTIC
TRANSFUSIONS DECREASED MATERNAL
MORTALITY SIGNIFICANTLY.
PAINFUL EVENTS, PE, PERINATAL
MORTALITY, NEONATAL DEATH AND
PRETERM BIRTH.
AND ALTHOUGH THERE WERE LOW
EVENT RATES FOR SOME
COMPLICATIONS AND THE AUTHORS
CONCLUDED THIS NEEDED FURTHER
STUDY, NONETHELESS, IT'S DATA
WITH END POINTS WE REALLY CARE
ABOUT.
SOME PEOPLE SAY YEAH, BUT IT WAS
A NEGATIVE RANDOMIZED CONTROL
TRIAL.
FIRST TO REMIND US ABOUT THE
HIERARCHY OF DATA, META ANALYSES
HAVE MORE WEIGHT THAN RANDOMIZED
CONTROL TRIALS.
THE 1998 RANDOMIZED CONTROL
TRIAL FROM A LONG TIME AGO
IDENTIFIED THAT TRANSFUSIONS
INITIATED ONCE PEOPLE BECAME
PREGNANT DID NOT CHANGE FETAL
OUTCOMES, AND THAT HAS BEEN USED
TO INTERPRET THE DATA AS A
NEGATIVE STUDY, BUT ACTUALLY
CHRONIC TRANSFUSIONS REDUCE
PAINFUL CRISES AND OTHER SICKLE
CELL COMPLICATIONS.
SO I GUESS I WOULD POSE TO YOU
IN THE PRESENCE OF EQUIPOISE
WHAT'S YOUR THRESHOLD FOR
INTERVENTION?
PATIENTS WHO ARE PREVIOUSLY
STABLE ON HYDROXYUREA EITHER
STARTED IN CHILDHOOD OR DUE TO
COMPLICATIONS, SHOULD WE PUT ALL
OF THEM ON TRANSFUSIONS?
WHAT ABOUT THINKING ABOUT THE
DOWNSTREAM EFFECTS OF PAIN?
I WORRY THAT WE DON'T THINK
ABOUT THIS WHEN WE THINK ABOUT
PAIN IN PREGNANCY.
SO IF WE PREVENT PAIN, WE
PREVENT HOSPITALIZATION,
THROMBOSIS, ACUTE CHEST,
MATERNAL FETAL OPIOID EXPOSURE,
IMPROVED QUALITY OF LIFE IN
PREGNANCY PERHAPS AND ALSO
REDUCE TOXIC STRESS ASSOCIATED
WITH RACISM WHEN YOU HAVE TO GO
INTO HEALTHCARE SYSTEMS THAT
AREN'T DESIGNED TO SERVE YOU
NECESSARILY.
MATERNAL ANEMIA IS A RECOGNIZED
RISK FACTOR FOR ADVERSE
OUTCOMES.
ALL OF OUR PATIENTS HAVE
MATERNAL ANEMIA.
IN THE STRESSFUL POSTPARTUM
PERIOD WHERE NOBODY SLEEPS AND
THE IMPACT OF YOUR TEASE MIGHT
DISEASE MIGHTGO UP, WE HAVE THEY
TO HELP STABILIZE THINGS.
I THINK ONE OF OUR GREATEST
PREOCCUPATIONS WITH USING
TRANSFUSIONS IN HIGH RESOURCE
SETTINGS FOR PREGNANCY IS THE
RISK OF ALEUM NIGHIZATION AND MY
STUDENT CLAIRE WILL BE
PRESENTING AN ORAL ABSTRACT
ABOUT THAT AT ASH.
THESE ARE TWO TOOLS TO HELP YOU
THINK ABOUT WHO SHOULD BE GOING
ON TRANSFUSIONS IN PREGNANCY.
THE AMERICAN AMERICAN SOCIETY OF
HEMATOLOGY GUIDELINES AND THE
RISK PREDICTION TOOL WHICH YOU
CAN PLAY WITH ON THE INTERNET,
IT TURNS OUT THESE TWO TOOLS
WORK ABOUT THE SAME AND I'M
REALLY LOOKING FORWARD TO THEM
VALIDATING THEIR TOOLS SO WE CAN
SHARE IT WITH OUR OBs.
THIS IS OUR APPROACH TO
TRANSFUSION AT JOHNS HOPKINS.
WE TRANSFUSE EVERYONE WITH SS
AND S BETA NULL THALASSEMIA
BEFORE PREGNANCY IF THEY'RE
PLANNERS AND THEY TELL US
THEY'RE GETTING PREGNANT, AND
ONCE THEY ARE PREGNANT, IF THEY
ARE NOT PLANNERS.
SO THE TRANSFUSIONS ARE HELPING,
WHAT ELSE SHOULD I WORRY ABOUT?
I KNOW MY TIME IS UP, I'M GOING
TO KEEP GOING AND THEN I'M GOING
TO BE DONE.
2 MORE MINUTES.
SO WE SHOULD WORRY ABOUT ACUTE
CHEST SYNDROME.
CAN WE REMEDIATE THIS BY PUTTING
PEOPLE ON TRANSFUSIONS AND CAN
WE GET INCENTIVE SPIROMETRY TO
ALL OF THE LABOR AND DELIVERY
UNITS IN THE COUNTRY?
I LEARNED AT A BIG SOCIETY OF
MATERNAL FETAL MEDICINE MEETING
A COUPLE MONTHS AGO THAT AMONG
THE SIX HERE 70 HOSPITALS --
NOBODY HAD A PROTOCOL AND SENT
FOR SPIROMETRY WHEN
HOSPITALIZED.
WE SHOULD BE THINKING ABOUT
BEING MORE AGGRESSIVE WITH
THROMBOPROPHYLAXIS IN THIS
POPULATION.
VTE RISK IS AS HIGH AS 11% IN
PREG Z THE ASH SICKLE CELL VTE
PREGNANCY GUIDELINES SAY THAT
THE THRESHOLD FOR INTERVENTION
WITH ANTI-COAGULATION
PROPHYLAXIS IS 1 TO 2%.
SO THESE GUYS ARE WAY OUTSIDE
THAT RISK.
THE THIRD TRY MOSTLY SUNNY TER
AND ANTENATAL RISK IS THE
HIGHEST TIME PERIOD AND BRITISH
GUIDELINES, CANADIAN GUIDELINES
AND NOW SOME U.S. CENTERS ARE
INITIATING PROAF LACKTIVE
ANTI-COAGULATION DURING THIS
TIME PERIOD.
FINALLY I JUST WANTED TO POINT
TO SOME DATA ABOUT GESTATIONAL
HYPERTENSIVE DISORDERS.
PLOOP IN OUR PABLOOD PRESSURE IS
IS LOW AND THE 140/90 THRESHOLD
CLEARLY DOESN'T APPLY TO THEM.
DRTHE DIASTOLIC BLOOD PRESSURESN
THIS COHORT WERE SO LOW THAT
THERE WAS NOT ONE MEASURE IN THE
WHOLE COHORT THAT EVER WAS A
DICE STOLG OF 90.
SO THAT DIASTOLIC BLOOD PRESSURE
OF 90 IS NEVER GOING TO DETECT
HYPERTENSION IN PREGNANT PEOPLE
WITH SICKLE CELL DISEASE.
WE ALSO DON'T TALK ABOUT WHAT'S
HAPPENING TO THE BABIES BORN TO
WOMEN WITH SICKLE CELL DISEASE.
IA PRELIMINARY STUDY, THEY LOOKD
AT THE BOSTON BIRTH COHORT AND
COMPARED IN A RIGOROUS MATCHED
WAY PHYSICAL AND COGNITIVE
DEVELOPMENTAL OUTCOMES OF BABIES
BORN TO WOMEN WITH SICKLE CELL
DISEASE COMPARED TO MATCHED
CONTROLS, AND YOU CAN SEE THERE
WERE DIFFERENCES IN WEIGHT,
OBESITY AND ADHD.
ARE WE BEING TAUING TO OUR
TALKING TO OUR PATIENTSABOUT TH?
THE LAST THING.
WE'RE MOVING TO ODESSA, TEXAS,
AND THAT'S NOT CLOSE ENOUGH TO
DR. ALISHA NURO, IS IT?
NO.
IT'S FIVE HOURS.
THIS IS MY FINAL POINT, WHICH IS
THAT WE CANNOT SOLVE THE RIDDLE
OF UNSAFE PREGNANCY FOR WOMEN
WITH SICKLE CELL DISEASE WITHOUT
COMPREHENSIVE SICKLE CELL
DISEASE CARE.
WHAT YOU CAN SEE ON THE LEFT IS
A MAP OF SICKLE CELL DISEASE
CENTERS, AND INDIVIDUALS WITH
SICKLE CELL DISEASE, AND ON THE
RIGHT, YOU CAN SEE MATERNITY
CARE DESERTS MAPPED OUT IN RED.
IT GIVES YOU A SENSE THAT
PARTICULARLY ODESSA, TEXAS, BUT
MUCH OF THE MIDDLE OF THE
COUNTRY AND MUCH OF THE SOUTH
ARE AT RISK FOR NOT BEING ABLE
TO PROVIDE HIGH QUALITY CARE IN
PREGNANT PEOPLE WITH SICKLE CELL
DISEASE SIMPLY BECAUSE THERE'S
NOT ANY MATERNITY CARE FOR
ANYONE.
THE CDC HAS RECENTLY PARTNERED
WITH US TO DEVELOP HANDOUTS FOR
OUR PATIENTS.
THIS IS A RESOURCE FOR YOU IN
YOUR CLINICS.
WE HAVE THREE GUIDELINES AND
THAT'S IT.
MULTIDISCIPLINARY CARE, WE CAN'T
DO IT WITHOUT OUR COLLEAGUES.
THIS PERSPECTIVE BLEW MY MIND.
DR. ANDY JAMES SAID TO ME, IT
NEVER EVEN OCCURRED TO ME THAT
THE PERSON IN THIS PICTURE WITH
SICKLE CELL DISEASE WAS THE
BABY.
WE SEE THE PROBLEMS A LITTLE BIT
DIFFERENTLY.
AND I THINK SEEING THE PROBLEMS
AND THE SOLUTIONS DIFFERENTLY IS
ONLY TO THE STRENGTHS OF OUR
PATIENTS AND TO THE BETTERMENT
OF OUR PATIENTS.
IN CONCLUSION, CONTEMPORARY
SICKLE CELL DISEASE CARE
REQUIRES US TO INCORPORATE
DIMENSIONS OF REPRODUCTIVE
HEALTHCARE, IT INVOLVES
TREATMENT DECISION LACED WITH
UNCERTAINTY AND THE INADEQUACY
OF FULLY FUNDED COMPREHENSIVE
SICKLE CELL CENTERS JEOPARDIZES
THE ABILITY TO PROVIDE THIS
CARE.
I THINK WE CAN HELP OUR YOUNG
PEOPLE MAKE REPRODUCTIVE LIFE
PLANS, IN PENCIL, AND PROVIDE
ITERATIVE COUNSELING TO THEM
ACROSS TIME, AND THIS CARRIES
INTERSECTIONAL,
MULTIDISCIPLINARY AND OFFERS
MANY JUK TOURS THAT REQUIRE
SHARED DECISION-MAKING.
THANK YOU.
[APPLAUSE]
THESE ARE SOME CLINICAL
RESOURCES, TAKE A SCREEN SHOT
AND WE'LL MOVE ON, BUT ALL OF
THESE THINGS HAVE TOOLS THAT YOU
COULD USE TO HELP YOUR PATIENTS.
AND YOU CAN READ -- YOU CAN
WATCH THAT WHOLE CONFERENCE ON
THE INTERNET.
>> THANK YOU SO MUCH.
THAT WAS SUCH A WONDERFULLY
DELIVERED AND VERY COMPREHENSIVE
TALK ON REPRODUCTIVE HEALTH
ISSUES IN BOYS AND GIRLS, MEN
AND WOMEN WITH SICKLE CELL
DISEASE.
I'M GLAD WE FOCUSED ON MEN AS
WELL.
AND JUST HIGHLIGHT THE FACT THAT
SO MUCH WORK IS NEEDED.
WE HAVE WOMEN IN JAMAICA WHO
REFUSE TO TAKE HYDROXYUREA
BECAUSE THEY WANT TO GET
PREGNANT.
CULTURALLY, SOCIALLY HAVING A
BABY IS VERY, VERY IMPORTANT TO
MANY, MANY WOMEN.
SO LOTS OF ISSUES.
WE DON'T HAVE ANY QUESTIONS
ONLINE AND JUST A REMINDER
ONLINE AUDIENCE TO CLICK ON
"SEND FEEDBACK" IF YOU HAVE ANY
QUESTIONS, RIGHT?
THAT'S THE -- RIGHT, NANCY,
RIGHT.
SO ANYBODY IN THE ONLINE
AUDIENCE WHO HAS A QUESTION OR A
COMMENT, SEND IT O ON THE SEND
FEEDBACK TAB ON YOUR ZOOM.
OKAY.
ANY QUESTIONS HERE OR COMMENTS
FOR LYDIA?
OKAY.
WE'LL HAVE GOOD CHATS OUTSIDE OF
THE SESSION, LYDIA.
I'M GOING TO INTRODUCE OUR NEXT
SPEAKER, WHO IS ALSO FROM
JAMAICA, JAMAICA IN THE
CARIBBEAN THIS TIME.
DR. BELINDA MORRISON, WHO IS A
CONSULTANT UROLOGIST AT THE
UNIVERSITY HOSPITAL OF THE WEST
INDIES, AND A SENIOR LECTURER
AND HEAD OF THE DIVISION OF
UROLOGY AT THE UNIVERSITY OF THE
WEST INDIES.
SHE COMPLETED HER UNDERGRADUATE
AND GRADUATE AND PO POSTGRADUATE
TRAINING AT THE UNIVERSITY OF
WEST INDIES MONA CAMPUS WITH A
ONE-YEAR RESIDENCY AT THE
UNIVERSITY OF TORONTO.
PROSTATE CANCER AND ANDROLOGY.
DR. MORRISON HAS MADE MANY LOCAL
REGIONAL AND INTERNATIONAL
PRESENTATIONS TO AUDIENCES IN
HER FIELD OF UROLOGY, INCLUDING
AT SCIFF IN PREVIOUS YEARS.
SHE'S EXTENSIVELY INVOLVED IN
RESEARCH, PARTICULARLY AS IT
RELATES TO ANDROLOGY AND SICKLE
CELL DISEASE.
DR. MORRISON COMPLETED A
TWO-YEAR RESEARCH FELLOWSHIP AT
THE SICKLE CELL UNIT IN JAMAICA,
AND CURRENTLY RUNS A MONTHLY
VOLUNTEER CLINIC AT HER UNIT.
SHE IS ALSO THE PAST PRESIDENT
OF JAMAICA UROLOGICAL SOCIETY,
IMMEDIATE PAST PRESIDENT OF TH
THE -- AMERICAN UROLOGICAL
ASSOCIATION AND SEXUAL MEDICINE
SOCIETY OF NORTH PLAIRK.
WELL SUITED TO SPEAK TO US ON
SPERM COUNTS AND MOTILITY.
DR. MORRISON, SHE WILL BE
PRESENTING VIRTUALLY.
THANK YOU.
-- AFFECTED PATIENTS WITH
SICKLE CELL DISEASE.
AS A UROLOGIST WORKING IN
JAMAICA, I'VE HAD QUITE A BIT OF
EXPOSURE TO PATIENTS WITH SICKLE
CELL DISEASE FOR AT LEAST THE
PAST 15 YEARS, AND SO TODAY, I'D
LIKE TO SHARE ON SOME OF THE
CHALLENGES THAT THESE PATIENTS
FACE, SPECIFICALLY AS IT RELATES
TO MALE FERTILITY, AND A PATIENT
I SAW SEVERAL YEARS AGO.
THERE ARE NO DISCLOSURES TO
DOCUMENT THIS MORNING.
SO I SPEAK ABOUT A 29-YEAR-OLD
MALE PATIENT WITH HOMOZYGOUS
SICKLE CELL DISEASE WHO
PRESENTED TO ME AT THE CLINIC AT
THE SICKLE CELL UNIT.
HE HAD A HISTORY OF PRACTICE
DURING HIS TEENAGE YEARS
MOSTLY -- EPISODES BUT NO
EPISODE RECENTLY.
HE HAD NEVER HAD ANY INVASIVE
TREATMENT FOR HIS PRIAPISM, AND
PRETTY MUCH MOST EPISODES HAD
RESOLVED SPONTANEOUSLY.
HE DENIED ANY HISTORY OF
ERECTILE DYSFUNCTION.
HE HAD OCCASIONAL PAINFUL CRISES
WHICH WERE PRETTY MUCH MANAGED
BY OUTPATIENT MANAGEMENT WL ORAL
ANALGESICS, AND HE CAME TO ME
EXPRESSING A DESIRE TO HAVE A
CHILD.
I TOOK A DETAILED HISTORY FROM
HIM AND WRECK RECOGNIZED WITH S
PARTNER HE HAD BEEN TRYING FOR
AT LEAST TWO YEARS AND HAD TRIED
WITH PREVIOUS PARTERS IN WITH NO
SUCCESS.
NO ALCOHOL USE, NO USE OF
ILLICIT DRUGS, HE HAD NO PRIOR
PELVIC OR INGUINAL SURGERY AS A
CHILD, NO EXPOSURE TO RADIATION
OR CHEMOTHERAPY, NO EXPOSURE --
NO VARICOCELES ON EXAMINATION
AND HE HAD A NORMAL EXAMINATION
IN TERMS OF GENITOURINARY --
GENITAL EXAMINATION.
NORMAL SIZED TESTES ON EXAM AND
IT WAS QUITE OBVIOUS THAT THIS
ISSUE WITH LACK OF HAVING A
CHILD WAS CAUSING GREAT DISTRESS
FOR HIM AND HIS PARTNER.
SO WHAT WE WENT FIRST FOR WAS A
SEMEN ANALYSIS, WHICH WE THINK
IS A BASELINE INVESTIGATION FOR
ANY PATIENT WHO IS HAVING ANY
ISSUE WITH FERTILITY.
THE FIRST DEMONSTRATED NO SPERM,
SO AZOSPERMIC.
WE DECIDED TO REPEAT AND THIS
CONFIRMED AZOOSP ERMIA.
THE PRESENCE OF SICKLE CELL
DISEASE MAY AFFECT HIS RISK FOR
FERTILITY.
I REFERRED BOTH HIM AND HIMSELF
FOR CONSULTATION ABOUT POTENTIAL
OPTIONS FOR ASSISTED
REPRODUCTIVE TECHNIQUES.
SO THIS IS WHAT WE'RE GOING TO
SPEAK ABOUT THIS MORNING.
WE'RE GOING TO BE SPEAKING ABOUT
MALE REPRODUCTIVE HEALTH AND
SEMEN ANALYSIS IN SICKLE CELL
DISEASE.
SO MALE REPRODUCTIVE HEALTH IN
SICKLE CELL DISEASE HAS BEEN
POORLY STUDIED.
ANY REVIEW OF THE LITERATURE
WILL SHOW VERY FEW STUDIES
LOOKING AT THE PRESENCE OF THESE
ABNORMALITIES AND ETIOLOGY AND
MANAGEMENT.
AND THIS MAY BE ONE OF THE
REASONS, BOTH PHYSICIANS AND
PATIENTS PRIORITY OVER THE
YEARS, POTENTIALLY
LIFE-THREATENING OR MON
COMMON -- OF SICKLE CELL
DISEASE, THIS COULD RANGE FROM
THE BOTHERSOME COMPLICATIONS O
OF -- WHICH WE SEE OFTEN FROM
PAIN FROM REPETITIVE PAINFUL
CRISES, FROM MAJOR CHRONIC
INFECTIONS, PULMONARY
COMPLICATIONS OR OTHERS, SO WHEN
PATIENTS ARE SICK AND THEY HAVE
THESE REPEATED ILLNESSES OR
ADMISSION TO HOSPITAL, CERTAINLY
THE -- WILL NOT BE ON FERTILITY.
NOW THE LACK OF A PARTNER DUE TO
THE COMPLICATION OF SICKLE CELL
DISEASE MAY ALSO BE ANOTHER
PARTNER.
SO THAT HAS NOT BEEN STUDIED
VERY GREATLY, HOW MANY OF THESE
PATIENTS HAVE PARTNERS OR HAVE
CHALLENGES FINDING PARTNERS.
AND THE CHALLENGES FINDING
PARTNERS MAY BE BECAUSE THEY
SPEND SO MUCH OF THEIR TIME IN
THE HOSPITAL, BUT THOSE WHO
DEVELOP LEG ULCERS ARE OFTEN
DEFORMITIES WE OFTEN SEE IN
SICKLE CELL DISEASE, THEY MAY
HAVE ISSUES CONCERNING THEIR
BODIES, THEIR COMFORT LEVELS
WITH THEIR BODIES, DEPRESSION
RELATED TO THEIR BODIES WHICH WE
KNOW IS A MAJOR ISSUE, SO THAT
MAY EVEN AFFECT THEIR INTEREST
OR THEIR ABILITY TO FIND ANOTHER
PARTNER, LET ALONE THINK ABOUT
FERTILITY.
THERE ARE ALSO LEGITIMATE
CONCERNS IN SOME OF THESE
PATIENTS REGARDING POTENTIAL
GENETIC TRANSMISSION OF THE
SICKLE CELL GENE TO THEIR
CHILDREN WHEN THEY SEE SOME OF
THE COMPLICATIONS THEY DEVELOP,
THEY MAY NOT BE COMFORTABLE IN
HAVING CHILDREN WHO MAY
POTENTIALLY HAVE THESE
COMPLICATIONS AS WELL.
NOW THE MEANS OF ASSESSMENT OF
MALE FERTILITY MAY NOT ALWAYS BE
SOCIALLY ACCEPTABLE.
AS WE SEE, THE PRIMARY TEST TO
DO IS A SEMEN ANALYSIS, AND MANY
MEN ARE NOT COMFORTABLE WITH THE
MEANS AT WHICH A SEMEN ANALYSIS
IS DONE.
THERE MAY BE EMBARRASSMENT IN
SOME OF THE MALES IN DISCUSSING
THE ISSUE WITH FERTILITY WITH
THEIR CAREGIVERS, AND THERE MAY
BE LACK OF KNOWLEDGE OF THE
PATIENTS AND THEIR CAREGIVERS ON
THE FERTILITY COMPLICATIONS THAT
THEY ARE SEEING IN SICKLE CELL
DISEASE.
SO, WE KNOW THAT WHO SAYS HEALTH
IS NOT SIMPLY A STATE OF
PHYSICAL WELL-BEING, IT'S A
STATE OF PHYSICAL, MENTAL AND
SOCIAL WELL-BEING, AND NOT
SIMPLY MERELY THE ABSENCE OF
DISEASE OR FERTILITY.
SO WE HAVE TO THINK NOT JUST
ABOUT THEIR PHYSICAL WELL-BEING
BUT WE MUST THINK ABOUT THEIR
MENTAL, PSYCHOLOGICAL, AND THEIR
REPRODUCTIVE CERTAINLY COMES
UNDER THE UMBRELLA OF COMPLETE
HEALTH.
AND AS PATIENTS WITH SICKLE CELL
DISEASE ARE LIVING LONGER, MUCH
BETTER AND HEAL HEALTHIER LIVES,
FERTILITY PRESERVATION MUST BE
ADDRESSED IN THESE PATIENTS.
SO FERTILITY IS DEFINED AS THE
ABILITY TO CONCEIVE CHILDREN.
INFERTILITY IS THE FAILURE TO
ESTABLISH A CLINICAL PREGNANCY
AFTER 12 MONTHS OF REGULAR AND
UNPROTECTED SEXUAL INTERCOURSE.
IN WOMEN WHO ARE WITH AGE OF 35
YEARS, THE TIME SPAN IS
SHORTENED TO SIX MONTHS.
SO ESSENTIALLY IF A PATIENT
COMES AND SAYS THEY'RE TRYING TO
HAVE A CHILD AND THEY'RE HAVING
A CHALLENGE, ONCE THAT PATIENT
IS LESS THAN 35 YEARS OF AGE,
YOU WOULD FIND OUT IF THEY HAVE
BEEN TRYING FOR 12 MONTHS OR
MORE AND IF THEY'VE BEEN TRYING
FOR OVER 12 MONTHS WITHOUT ANY
SUCCESS, THEN WE WOULD SAY THAT
THEY ARE LIKELY TO HAVE
INFERTILITY OR SUBFERTILITY.
IN THE GRAND SCHEME OF THINGS,
FERTILITY -- INFERTILITY AFFECTS
MAYBE ABOUT 10% OF COUPLES
WORLDWIDE, AND THE MALE FACTOR
IS FOUND -- A SOLE MALE FACTOR
IS FOUND IN ABOUT 20% OF CASES,
ANOTHER 20 TO 30% OF CASES IS
COMBINED MALE AND FEMALE.
SO OVERALL, A MALE FACTOR IS
PRESENT IN APPROXIMATELY 50% OF
CASES.
AND SICKLE CELL DISEASE, NOT A
LOT OF DATA ON THE PREVALENCE OF
INFERTILITY, BUT CERTAINLY FROM
ONE STUDY THAT WAS REPORTED BY
STEVENSON, WE SEE THAT 16.9% OF
MALES AND 23% OF FEMALES HAVE
SELF-REPORTED INFERTILITY, AND
CERTAINLY THIS MAY BE AN
UNDERESTIMATE AS MORE PATIENTS
ARE EVALUATED AND DIFFERENT
TYPES OF STUDIES ARE DONE, WE
MAY SEE THE RATES ARE MUCH
HIGHER.
SO DEFINITELY WE CAN SEE
STARTING WITH THESE RATES WHICH
I BELIEVE ARE UNDERREPORTED,
THEY'RE DEFINITELY MORE THAN
WHAT IS CONSIDERED IN THE NORMAL
POPULATION.
SO WHAT TYPE OF -- WE CAN LOOK
AT MEN IN FERTILITY AFFECTED
FROM A CENTRAL LEVEL, THE
HYPOTHALAMUS, PITUITARY LEVEL,
IN TERMS OF HORMONAL CAUSES.
WE MAY SEE IT BE DIRECTLY AT A
LEVEL OF THE GONADS, OR AT THE
LEVEL OF THE TUBES WHERE SPERM
IS RELEASED.
SO THE CENTRAL LEVEL HORMONAL
PROBLEMS MAY BE PITUITARY
PROBLEMS, THEY MAY BE DUE TO A
LACK OF FSH OR DUE TO ANABOLIC
STEROID USE.
AT THE LEVEL OF THE GONADS,
WHERE THERE MAY BE TOXICITY TO
THE DOUGH IN ADDITIONS, EITHER
FROM EXPOSURE TO CHEMOTHERAPY OR
RADIATION, EITHER FROM TRAUMA TO
THE TESTES, EITHER SEVERE
INFECTIONS, SEXUALLY TRANSMITTED
INFECTIONS, CONGENITAL REASONS,
MAYBE AN UNDESCENDED TESTES,
TORSION THAT IS NOT QUICKLY
TREATED RESULTING IN EITHER
ISCHEMIA TO THE TESTES OR AN
ORCHIECTOMY.
GENETIC OR HO -- MIGHT BE SEEN N
QUITE A FEW UNKNOWN CAUSES OF --
THERE ARE ALSO CASES RELATED TO
VASECTOMY, WHICH IS A REQUEST A
PATIENT WOULD MAKE BUT
SOMETIMES -- PATIENTS MAY
DEVELOP ANTISTERM ANTIBODIES, IN
IN PERSONS WHO HAVE HAD
VASECTOMY OR INJURIES TO THE
TESTES, AND OF COURSE SEXUAL
PROBLEMS, ERECTILE DYSFUNCTION,
RETROGRADE OR ANEJACULATION,
INFREQUENT INTERCOURSE,
RETROGRADE EJACULATION, AND
NEUROLOGICAL PROBLEMS AS WE SEE
IN -- OR SOME MEDICATIONS.
THERE ARE A WHOLE HOST OF CAUSES
OF MALE INFERTILITY.
AS WE MENTIONED BEFORE, THE
BASIC -- IS A THOROUGH
REPRODUCTIVE HISTORY, BUT AT
LEAST ONE SEMEN ANALYSIS.
THIS IS USUALLY DONE AFTER A
PERIOD OF ABSTINENCE FOR TWO TO
THREE DAYS, AND THEN BY
MASTURBATION, PATIENT PRODUCES A
SAMPLE.
A LOT OF PATIENTS ARE NOT
COMFORTABLE WITH THIS, I WILL
SAY, IN MY EXPERIENCE, AND SOME
PATIENTS PREFER TO USE THE
ANTISPERM CIDAL CONDOMS, BUT
EVEN SO, SOMETIMES THAT'S NOT
CONVENIENT FOR THEM.
WHAT DOES WHO SAY THE REFERENCE
VALUES FOR NORMAL SEMEN ANALYSIS
ARE?
SO THERE HAVE BEEN A CHANGE OVER
THE YEARS IN TERMS OF WHAT ARE
CONSIDERED NORMAL REFERENCE
RANGES FOR ANALYSIS OF THE
SEMEN.
SO MOST PEOPLE WHEN THEY THINK
ABOUT A SEMEN ANALYSIS, THEY
SIMPLY THINK OF WHAT IS CALLED A
SPERM COUNT, BUT WE HAVE VARIOUS
THINGS WE LOOK AT.
THE VOLUME CAN GIVE US A PICTURE
AS TO WHETHER THERE IS AN
OBSTRUCTIVE CAUSE SUCH AS A
NON-OBSTRUCTIVE OR OR
OBSTRUCTIVE CAUSE, UNOBSTRUCTIVE
CAUSE, ONE MAY SEE SOMEONE WHO
HAS HAD PREVIOUS TESTICULAR OR
GONADAL -- INGUINAL SURGERY,
PERHAPS AS A CHILD AND THE
SPERMATIC CORD HAS BEEN LIGATED
OR TIED OFF.
OBSTRUCTIVE CAUSES MAY BE SEEN
IN PERSONS WHO'VE HAD
EPIDIDIMITIS IN THE PACE AND
OTHER CAUSES THAT CAN LEAD TO
LOW VOLUME.
SO WE LOOK AT THE VOLUME, THE
SPERM CONCENTRATION, WHAT
EVERYONE CALLS A COUNT.
AND IN 1990 M 1999, THIS SHIFTEN
IN 2010 TO 50 MILLION, AND THE
MOST RECENT UPDATED VERSION OF
THE WHO SUGGESTS 60 MILLION AS A
MINIMUM FOR THE CONCENTRATION.
FOR THE TOTAL AT LEAST GREATER
THAN 50% WERE CONSIDERED NORMAL,
THEN IT WAS SHIFTED DOWN TO 40,
THEN IT INCREASED TO 42.
AND FOR NORMOZOOSPERMIA, THERE
WAS MORE, BUT WE'LL FOCUS MAIN
LEA ON CON SIN TRAIT 16 TRAITIO-
STUDIES HAVE DOCUMENTED THAT
MALES AND FEMALES WITH SICKLE
CELL DISEASE HAVE DELAYED
PUBERTY.
AND PUBLISHED IN THE NEW ENGLAND
JOURNAL IN 1984 SUGGESTS THIS
MAY BE A CONSTITUTIONAL DELAY
SINCE YES THEY DO HAVE A DELAYED
PUBERTY, MAYBE BY TWO YEARS OR
MORE, THAN THE RISK OF THE
ADOLESCENT NONE SICKLE CELL
COHORTS, HOWEVER, THINGS SEEM TO
NORMALIZE AFTER.
OTHERS THOUGHT IT MAY BE DUE TO
THE CHRONIC ANEMIA, CHRONIC
DISEASE, AND OTHERS HAVE THOUGHT
IT MAY BE ENDOCRINE-RELATED
WHERE THEIR IS INCREASE IN
HORMONES AND THIS HAS BEEN
DOCUMENTED IN LOCAL STUDIES IN
JAMAICA THAT IN ADOLESCENTS,
THERE ARE HIGHER LEVELS THESE
GONADOTROPINS SUGGESTING AN
ENDOCRINE CAUSE BUT WHAT WE'RE
NOT SURE OF THE EXACT CAUSE OF
THE DELAY, AND IF IT CONTINUES
INTO ADULTHOOD AND HOW IT
AFFECTS THEM, PARTICULARLY THE
MEN.
SO LET'S LOOK AT SOME OF THE
STUDIES THAT HAVE BEEN
PUBLISHED.
IN AN EXTENSIVE SEARCH OF THE
LITERATURE, WHAT I FOUND WERE
SEVEN PUBLISHED PAPERS LOOKING
AT SEMEN ANALYSIS AND SICKLE
CELL DISEASE OVER THE YEARS.
FIRLS PUBLISHED PAPER WAS IN
1974 BY FRIEDMAN, AND HE STUDIED
EIGHT YOUNG BLACK MEN, AGE RANGE
WAS FROM 22 TO 34 YEARS, WHO HAD
SICKLE CELL DISEASE.
SEVEN HAD HOMOZYGOUS SICKLE CELL
DISEASE, ONE HAD S BETA THAL.
THEY TOOK A HISTORY ON DISEASE
SEVERITY, ONSET OF PUBERTY,
SEXUAL HISTORY AND PATERNITY.
THEY ALSO EXAMINED THEIR FSH,
THREE OF THESE FOUR PATIENTS HAD
OLIGOSPERMOUS, LESS THAN
20 MILLION PER ML.
SPERM CONCENTRATION, SORRY.
BUT THEY ALL HAD NORMAL
TESTOSTERONE FOR THEIR AGE.
LUTEINIZING HORMONE, FSH
REGULATOR HORMONE FOR SPERM
PRODUCTION IN A MALE.
FSH WAS NORMAL BUT LHIF WE LOOK
AT THE TABLE FROM THIS PAPER, WE
SEE PATIENTS NUMBER ONE, TWO,
THREE AND SIX HAD SEMEN ANALYSIS
DONE, AND HERE AT THE BOTTOM,
THEY'LL TELL YOU WHAT THE
REFERENCE RANGE IS AT THAT TIME.
NORMAL WOULD HAVE BEEN GREATER
THAN 20 MILLION AND WHAT WE SEE
IS PATIENT ONE HAD A COUNT OF
2 MILLION, PATIENT TWO HAD A
COUNT OF 14.2 MILLION, PATIENT
THREE HAD 8.8.
ONLY PATIENT SIX WHO HAD A
NORMAL SPERM CONCENTRATION AND
52 MILLION.
WE SEE THAT MOTILITY WAS -- IN
ONLY ONE PATIENT WAS 30 TO 50%.
VOLUME AT THAT TIME WAS
CONSIDERED NORMAL IF IT WAS 3 TO
5 MLs AND IT WAS LOWER IN
PATIENT ONE AND PATIENT SIX.
SO ESSENTIALLY WE SEE THERE ARE
ABNORMAL PARAMETERS IN THREE OF
THESE FOUR PATIENTS.
BUT OF COURSE THIS IS A SMALL
CASE SERIES, ONLY FOUR PATIENTS.
THOUGH THEY SUGGESTED THAT THEY
COLLECTED DATA ON THEIR HISTORY
AND SEXUAL HISTORY, THERE WAS NO
DOCUMENTATION OF OTHER POSSIBLE
CAUSES OF SUBFERTILITY AND
AUTHORS POSTULATED ISCHEMIA
SECONDARY TO SICKLING WAS A
CAUSE.
IF IT WAS A PRIMARY CAUSE, FSH
LEVEL WOS HAVE BEENS WOULD HAVED
THIS WAS NOT THE CASE.
THE SECOND PAPER PUBLISHED WAS
IN 1980, SMALL CASE SERIES AS
WELL.
PATIENTS WITH SICKLE CELL
DISEASE OR SEMEN ANALYSIS WERE
REPORTED.
WHAT THEY SAW WAS THERE WAS
REDUCED FORWARD PROGRESSION, SO
MOTILITY WAS AFFECTED AND
MORPHOLOGY HAD A STRESS PATTERN,
AND BASED ON THIS PATTERN, WHICH
THE AUTHOR SAID IT MIMICKED WHAT
WE SEE IN VARICOCELES, THEY
THOUGHT A TESTY CAL HYPOXIA WAS
A CAUSE, AGAIN SUGGESTING A
PRIMARY CAUSE WAS THE RESULT.
THIRD PAPER PUBLISHED IN THE
LANCET IN 1981, 40 -- MEAN AGE
OF 20 YEARS, AND THEY WERE SEEN
IN AN OUTPATIENT DEPARTMENT IN
NIGERIA.
ALL PATIENTS HE TIME WERE IN
STEADY STATE OF THE DISEASE, AND
THEY TOOK A HISTORY ON THEIR
AGE, MARITAL STATUS, SEXUAL
EXPERIENCE AND WHETHER THEY'D
FATHERED CHILDREN OR NOT, BUT
NONE OF THIS WAS EVER CONFIRMED
OR CORROBORATED.
TWO SEMEN ANALYSES WERE DONE IN
EACH PATIENT AFTER A PERIOD OF
ABSTINENCE.
HOWEVER OF THE 40 PATIENTS, ONLY
23 PROVIDED SAMPLES FOR SEMEN,
AND THERE WERE 25 MALE CONTROLS
AND THESE CONTROLS WERE PERSONS
WHO HAD WIVES OR PARTNERS
ATTENDING AN ANTENATAL CLINIC AT
THE TIME.
OF THE PATIENTS, FOUR WERE
MARRIED WITH NO CHILDREN IN
WEDLOCK, SO THESE WERE THE
PATIENTS WITH SICKLE CELL
DISEASE.
FOUR WERE MARRIED BUT NO
CHILDREN IN WEDLOCK.
BUT THREE OF THESE REPORTED THAT
THEY HAD CHILDREN OUTSIDE OF
WEDLOCK.
36 WERE UNMA UNMARRIED.
10 HAD HISTORY OF COITUS, AND
ONE CHILD OF THE 36 UNMARRIED.
NO PATIENT WITH SICKLE CELL
DISEASE HAD A SEMEN ANALYSIS
THAT WAS NORMAL FROM THIS STUDY.
SO THE ABNORMALITIES WERE EITHER
IN THE CONCENTRATION WHICH WAS
LOWER, THE TOTAL COUNT, THE
MOTILITY, AND THE MORPHOLOGY.
AND THE CAUSE AGAIN WAS
SUGGESTED TO BE POTENTIALLY
PRIMARY SIMPLY BECAUSE THIS SAME
GROUP HAD STUDIED SEVERAL OTHER
PATIENTS WITH SICKLE CELL
DISEASE AND THEY LOOKED AT
THINGS LIKE THE FSH, LH AND
TESTOSTERONE, AND WHAT THEY
FOUND IN THAT STUDY, WHICH WAS
PUBLISHED IN A MEDICAL JOURNAL
IN 1987, WAS THAT THEY HAD LOWER
TESTOSTERONE LEVELS AND ELEVATED
FSH LEVELS.
AND SO IT WAS THOUGHT THAT THE
CAUSE WAS PRIMARY.
SO THOUGH THE FSH LEVELS WERE
NOT DONE IN THIS PARTICULAR
STUDY GROUP, IN ANOTHER STUDY
FROM THE SAME AUTHORS, THEY SAW
THAT FSH LEVELS WERE ELEVATED.
SO THEY POSTULATED THIS MAY BE A
PRIMARY FAILURE.
WE HAD ANOTHER STUDY PUBLISHED
IN 1988, WHERE WE HAD 25
PATIENTS WITH SICKLE CELL ANEMIA
COMPARED TO 25 WITH HBAA, AND
ALL PATIENTS WITH SICKLE CELL
DISEASE HAD EITHER -- AN
ABNORMALITY IN EITHER EJACULATE
VOLUME, SPERM DENSITY OR SPERM
MORPHOLOGY.
AND IT WAS SIGNIFICANTLY
REDUCED.
AGAIN THEY POSTULATED THAT IT
MAY BE A PRIMARY DYSFUNCTION AS
WELL AS -- THEY FOUND VOLUME OF
SEMEN WAS LOWERED AND WE KNOW
THAT VOLUME COMES PRIMARILY FROM
PROSTATE AND SEMINAL VESICLES SO
THEY FIGURED THAT IT WAS A
GENERAL PRIMARY CAUSE.
IN 1995, PAPER LOOKING AT
22 PATIENTS WITH SICKLE CELL
DISEASE ALL STEADY STATE, 20
CONTROLS, THESE WERE YOUNG
PERSONS BETWEEN THE AGES OF 18
TO 40 YEARS AND EXCLUDED
ANYTHING THAT WOULD BE
CONSIDERED A CONFOUNDER OR
SOMETHING THAT COULD POTENTIALLY
ALSO CAUSE ABNORMAL FERTILITY IN
THESE PATIENTS.
THEY TOOK A HISTORY LOOKING AT
THEIR SEXUAL FUNCTION, MARITAL
STATUS AND PATERNITY.
PATIENTS WERE WEIGHED AND
MEASURED AND TESTOSTERONE, FSH,
LH AND PROLACTIN WERE MEASURED
AND TWO SEMEN ANALYSIS DONE
AFTER PERIOD OF ABSTINENCE.
WHAT DID THEY FIND?
WE LOOK AT THE SICKLE CELL
PATIENTS VERSUS CONTROL, YOU SEE
PATIENTS WITH SICKLE CELL
DISEASE HAD SIGNIFICANTLY LOWER
SPERM DENSITY, SO THIS WOULD BE
CONSIDERED CONCENTRATIONS --
DIFFERENCE IN TERMINOLOGY AT THE
TIME, CONCENTRATION WAS 21.4,
COMPARED TO 69 IN THE CONTROLS.
OF COURSE WE SEE THE STANDARD
DEVIATION IS QUITE HIGH, SO WE
HAD A WIDE RANGE.
MOTILITY WAS LESS, 42% VERSUS
73% OF THE CONTROLS, AND
MORPHOLOGY WAS ALSO MUCH LOWER
AS WELL AS TESTICULAR VOLUME.
10 OF THE 20 PATIENTS IN THIS
STUDY EITHER HAD AN ISSUE WITH
EITHER LOW LIBIDO, ERECTILE
DYSFUNCTION OR PRIAPISM, ALL
THINGS WE KNOW CAN AFFECT
FERTILITY.
ONLY ONE CONTROL HAD AN ISSUE
WITH ERECTILE DYSFUNCTION.
ONLY ONE PATIENT WITH SICKLE
CELL DISEASE REPORTED HAVING
FATHERED A CHILD WHEREAS NINE
CONTROLS HAD.
SO YOU KNOW, WHEN THEY LOOKED AT
OTHER DETAILS LIKE THE
TESTOSTERONE LEVEL THE, FSH, LH,
PROLACTIN LEVELS, WE FIND
TESTOSTERONE LEVELS WERE
SIGNIFICANTLY LOWER IN PATIENTS
WITH SICKLE CELL ANEMIA, THIS
HAS BEEN KEEPING WITH SEVERAL
OTHER STUDIES THAT HAVE BEEN
PUBLISHED OVER THE YEARS.
FSH, HOWEVER, WAS NOT
SIGNIFICANTLY HIGHER.
THERE WAS A TREND TO IT BUT IT
WAS NOT OF STATISTICAL
SIGNIFICANCE.
AND LUTEINIZING HORMONES LEVELS
WERE HIGHER AS WELL.
THE AUTHORS FOUND THAT THERE WAS
A DIFFERENCE WITH THE LEVELS OF
THE TESTICULAR VOLUME,
TESTOSTERONE LEVELS AND SPERM
COUNT DEPENDING ON THE AGE OF
THE PATIENT.
SO IF WE LOOK AT THIS TABLE,
PATIENTS WITH SICKLE CELL ANEMIA
OVER 25 YEARS HAD A HIGHER LEVEL
OF TESTOSTERONE, OF TESTICULAR
VOLUME, OF EVEN BMI THAN THOSE
WHO WERE LESS THAN 25.
THERE WAS NOT A SIGNIFICANT
DIFFERENCE IN THEIR SPERM COUNT,
EVEN THOUGH THERE WAS A TREND TO
THAT.
SO WHAT THEY THOUGHT WAS THAT
WHATEVER CAUSED THE INSULT IN
THESE PATIENTS PROBABLY FROM
ADOLESCENCE IMPROVED WITH TIME
BUT IT CERTAINLY DID NOT
NORMALIZE.
THEY DID NOT ASSESS DISEASE
SEVERITY IN THEIR PATIENTS AND
THIS ALSO IS A CROSS-SECTIONAL
STUDY.
SO THE LARGER SERIES TO DATE
LOOKING AT SEMEN ANALYSIS IN
SICKLE CELL DISEASE IS THAT
PUBLISHED IN -- THIS WAS PUBL
PUBLISHED SOMETIME LATER, AND IN
2008, AND THEY HAD 108 SEMEN
ANALYSIS FROM 44 PATIENTS.
FROM 4 PATIENTS.
44 PATIENTS.
THE MAIN AIM OF THE PAPER WAS TO
LOOK AT THE INFERENCE OF SICKLE
CELL DISEASE AS WELL AS
TREATMENT WITH HYDROXYUREA AND
SPERM PARAMETERS.
WE KNOW THAT THERE ARE A FEW
STUDYS THAT HAVE BEEN DONE THAT
HAVE SUGGESTED THAT THERE IS NO
CHANGE AND SEVERAL OTHERS WHICH
HAVE SUGGESTED THAT HYDROXYUREA
DOES IMPACT SEMEN PARAMETERS IN
SICKLE CELL DISEASE.
FROM THIS STUDY, 91% OF PATIENTS
WITH PRE-TREATMENT SEMEN
ANALYSIS HAD AT LEAST ONE
ABNORMALITY, AND ALL SEMEN
PARAMETERS WERE WITHIN SIX
MONTHS OF TREATMENT BUT AFTER
STOPPING TREATMENT, THE
PARAMETERS SEEMED TO RECOVER,
BUT NOT -- AFTER STOPPING
TREATMENT, THE PARAMETERS DID
NOT SEEM TO RECOVER TO
PRE-TREATMENT LEVELS.
SO HERE WE HAVE A TABLE FROM
THAT SAID PAPER WHERE WE LOOK AT
THE VOLUME OF E EJACULATE, DIDNT
SEEM TO BE A SIGNIFICANT DROP,
3MLs VERSUS 2.68 TO 2.99, ALL
USING CURRENT REFERENCE
GUIDELINES WITHIN THE NORMAL
RANGE, BUT WHAT WE SEE IS THAT
THE SPERM CONCENTRATION WAS 38.5
PLUS OR MINUS 43, SO A WIDE
RANGE FROM .02 TO 2.80.
THIS IS PRE-TREATMENT.
WITHIN SIX MONTHS OF TREATMENT
CIRCLES CAN'T DROP TO 2.66,
AFTER TREATMENT INCREASED A BIT,
BUT STILL USING THE GUIDELINES
WHEN THIS STUDY WAS DONE WOULD
HAVE BEEN LOWER.
CERTAINLY A DROP IN YOUR SPERM
CONCENTRATION OVER THE PERIOD OF
TIME.
IF WE USE OUR CURRENT WORLD
HEALTH ORGANIZATION GUIDELINES
OR REFERENCE VALUES, 18.46 WOULD
BE CONSIDERED NORMAL.
BUT IF WE COMPARE TO THE
PRE-TREATMENT, 38.5 TO 18.46,
THERE'S A DEFINITE DROP.
TOTAL COUNT FOR THIS WOULD BE
THE CONCENTRATION DRK A MULTIPLE
OF A CONCENTRATION IN VOLUME,
114 WENT DOWN TO 7, WENT UP TO
61 AFTER TREATMENT, TWO YEARS
AFTER TREATMENT.
AND MOTILITY DID NOT APPEAR TO
BE SIGNIFICANTLY AFFECTED.
SO THIS IS JUST ONE INDIVIDUAL
PATIENT WHERE WE LOOK AT THE
PARAMETERS BEFORE TREATMENT,
THREE SAMPLES WERE TAKEN.
AFTER TREATMENT, AFTER FOUR
YEARS, AND AFTER FIVE YEARS.
AND WE SEE THAT THE SPERM
CONCENTRATION REDUCED FROM
37.2 TO 17.5, TO 31.6, EVEN
BEFORE TREATMENT, AND AFTER FOUR
YEARS OF TREATMENT, 3.3 TO 1.2.
SO THERE APPEAR TO BE SOME
IMPACTS ON THIS PATIENT WHICH
DID NOT NORMALIZE AFTER
TREATMENT WAS STOPPED.
SO WE KNOW HYDROXYUREA CAN --
THERE APPEARS TO BE REVERSIBLE
DECREASE IN SPERM COUNT, NORMAL
SPERM MORPHOLOGY AND MOTILITY.
SO WE SEE HERE THAT THE IMPACT
OF TREATMENT ON THE SPERM
PARAMETERS IN A PATIENT WHO
ALREADY MAY HAVE SOME METABOLIC
CAUSE FOR THEIR IMPAIRED
PARAMETERS.
A GROUP IN INDIA DID AGE MATCHED
CASE CONTROL STUDY, YOUNG
PATIENTS, 18 TO 45 YEARS, ALL
PATIENTS WERE IN STEADY STATE,
AND THEY EXAMINED THE PATIENTS
AND THEY LOOKED AT SPERM COUNT,
AND THEY LOOK AT SEMEN ANALYSIS.
SURPRISINGLY THIS IS THE ONLY
PAPER IN LITERATURE THAT HAS
DOCUMENTED THAT PATIENTS WITH
SICKLE CELL DISEASE HAVE A
HIGHER COUNT THAN THOSE WITHOUT
SICKLE CELL DISEASE.
IF YOU LOOK AT THIS PAPER
PUBLISHED HERE, THE TABLE
SUGGESTS THAT THE TOTAL COUNT
WAS 57.6 IN THE SICKLE CELL
PATIENTS VERSUS 39.75 IN
NON-SICKLE CELL PATIENTS.
MOTILITY WAS HIGHER, AS WELL AS
MORPHOLOGY WAS NORMAL.
THE AUTHORS DID DOCUMENT THAT
INFERTILITY WAS QUITE COMMON IN
THIS REGION SAMPLE, NOT
WITHSTANDING, THEY DID FIND HIGH
LEVELS OF NORMAL SEMEN ANALYSIS
PATTERNS IN THESE PATIENTS.
SO WHAT'S ETIOLOGY OF NORMAL
SEMEN PARAMETERS IN SICKLE CELL
DISEASE?
IF WE LOOK AT THESE PAPERS,
WE'LL SEE THAT THERE ARE A
NUMBER OF -- ETIOLOGIES.
ONE ISCHEMIA DUE TO SICKLING, SO
ISCHEMIA -- TESTICLE ISCHEMIA,
THERE HAVE BEEN A FEW CASE
REPORTS WITH PATIENTS WHO HAVE
HAD ISCHEMIA LEADING TO EVEN
INFARCT IN SICKLE CELL DISEASE,
SO THAT'S ONE THEORY.
TESTICULAR HYPOXIA IS THOUGHT TO
BE ONE.
OTHERS THINK IT MAY BE DUE TO
DYSFUNCTION OF ACCESSORY GLANDS.
THERE MAY BE A SECONDARY
FAILURE, NOT NECESSARILY PRIMARY
FAILURES, IN PREVIOUS -- DUE TO
CENTRAL INFARCTS EITHER OF THE
HYPOTHALAMUS OR PITUITARY GLAND,
REDUCED LIBIDO WITH --
HYPOGONADISM SO LACK OF INTEREST
IN SEX MAY MEAN LACK OF STRONG
ERECTIONS AND WITHOUT
COPULATIONS PATIENTS CAN'T GET
PREG NATE.
PREGNANT.
MAY BE IATROGENIC AS WE JUST SAW
DUE TO HYDROXYUREA OR CONDITION
BEFORE STEM CELL TRANSPLANTS FOR
THESE PATIENTS.
SO WHAT ARE OUR SUGGESTIONS,
WHAT ARE MY SUGGESTIONS?
I SUGGEST THAT WE EVALUATE ALL
ADULT MALES WITH SICKLE CELL
DISEASE.
WE MUST HAVE A DISCUSSION WITH
THEM ABOUT DESIRE FOR FERTILITY,
AND IF THEY'VE EVER BEEN TESTED
OR IF THEY DO HAVE CHILDREN.
I THINK IF INFERTILITY IS FOUND
AFTER DOING A SEMEN ANALYSIS,
ETIOLOGY MUST BE DETERMINED, AND
WE CONSIDER POSSIBLE
CRYOPRESERVATION IN ELIGIBLE
PATIENTS BEFORE BEGINNING
HYDROXYUREA OR BEFORE EVEN DOING
STEM CELL TRANSPLANTS.
IN THE FUTURE, I THINK PATIENT
EDUCATION IS VERY IMPORTANT.
A VERY LOVELY PAPER THAT WAS
PUBLISHED FROM THE CLINICAL
TRIALS GROUP LAST YEAR JUNE
LOOKED AT FERTILITY TESTING IN
MALES WITH SICKLE CELL DISEASE
AND THEIR CAREGIVERS.
WHAT WE SAW WAS THAT MAYBE
KNOWLEDGE LEVEL COST HAVE
IMPROVED BETWEEN THE CAREGIVERS
AND THE PATIENTS BUT THERE WAS
CERTAINLY A STRONG DESIRE
FOREKNOWLEDGE ABOUT FERTILITY IN
THESE PATIENTS, SO I THINK
EDUCATION IS VERY IMPORTANT,
EVEN FROM LEVEL OF ADOLESCENCE.
I THINK WE NEED TO DEFINITELY DO
FURTHER STUDIES ON ETIOLOGY.
THERE'S MUCH MORE THAN JUST
LOOKING AT THINKING THAT IT MAY
BE DUE TO INFARCTION OR
ISCHEMIA, BUT PERHAPS MANY OTHER
CAUSES ARE RESPONSIBLE.
CERTAINLY IN THE GRAND SCHEME OF
FERTILITY EVALUATION AND
FERTILITY ETIOLOGY, IN GENERAL,
IN THE GENERAL POPULATION,
OXIDATIVE STRESS IS A MAJOR
CAUSE, AN EMERGING MAJOR CAUSE.
KURNS EVIDENCE LINKS ACTIVE
STRESS TO MALE INFERTILITY,
SPERM DAMAGE, INCREASED RISK OF
RECURRENT ABORTIONS AND GENETIC
DISEASES.
IN PATIENTS OF PATIENTS WITH
HIGH LEVELS OF OXIDATIVE STRESS,
THEY SAY THIS PERHAPS COULD BE
ONE OF THE MAJOR CAUSES IN THEM.
WHAT HAS BEEN FOUND IN THOSE
PERSON WITH OXIDATIVE STRESS IN
THE GENERAL POPULATION AND
NON-SICKLE CELL POPULATION,
EARLY IDENTIFICATION POSSIBLY
EVEN TREATING THE OXIDATIVE
STRESS MAY REDUCE MALE
INFERTILITY.
SO IN SUMMARY, ABNORMALITIES OF
SEMEN PARAMETERS ARE COMMON IN
SICKLE CELL DISEASE.
EXACT ETIOLOGY REMAINS ELUSIVE.
PATIENT EDUCATION AND EVALUATION
IS IMPERATIVE.
AND SPERM CRYOPRESERVATION
SHOULD BE CONSIDERED PRIOR TO
USE OF NEWER TREATMENTS.
I THANK YOU.
>> KNEW THANK YOU SO MUCH, BEL,
FOR A GREAT LOOK AT SEMEN AND
ISSUES IN SICKLE CELL DISEASE
MALES.
SHE'S NOT AVAILABLE FOR
QUESTIONS BUT IF YOU DO HAVE, IF
THE AUDIENCE HAS ANY QUESTIONS
THAT WE WILL HAVE THEM ANSWERED
BY HER.
WE ARE RUNNING -- 2 MINUTES
BREAK, IS THAT OKAY WITH
EVERYONE?
AND COME RIGHT BACK BY 3:15 TO
START OUR LAST SESSION.
TAKE A STRETCH BREAK, PLEASE.
THANK YOU.
DURING THE PANDEMIC.
THE COVID-19 PANDEMIC CHANGED
ALL OUR NORMS.
WE WERE NOW LIVING IN A WORLD OF
LOCKDOWNS, SOCIAL DISTANCING,
MASKING AND HAND HYGIENE.
DELIVERY OF SAFE AND EFFECTIVE
HEALTHCARE BECAME A CHALLENGE,
ESPECIALLY FOR VULNERABLE
POPULATIONS, AND TELEHEALTH WAS
THE SOLUTION.
THERE WAS AN EXPLOSION OF
TELEHEALTH SERVICES WORLDWIDE,
AS IT ALLOWED HEALTHCARE
PROVIDERS TO CONTINUE TO CARE
AND MANAGE PATIENTS AT A SAFE
DISTANCE, DECREASING THEIR RISK
AND EXPOSURE TO INFECTION.
TELEHEALTH IS NOT A NEW CONCEPT.
IT'ITS HISTORY ACTUALLY DATES BK
TO THE 1960s, AND KEY ELEMENTS
OF ITS DEFINITION ARE, ONE, IT
IS A TOOL FOR THE DELIVERY OF
HEALTHCARE, IT IS NOT THE
HEALTHCARE SERVICE IN ITSELF.
TWO, IT PROVIDES HEALTHCARE AT A
DISTANCE, AND THREE, IT USES ICT
TECHNOLOGIES FOR INFORMATION
EXCHANGE.
IN ITS STRICTNESS SENSE,
TELEHEALTH REFERS TO INFORMATION
AND COMMUNICATION, ACCESS AND
INCREASING COSTS HAVE BEEN WELL
DESCRIBED.
SIMILARLY, ITS CHALLENGES AND
BARRIERS ARE ALSO WELL-KNOWN.
AND IMPORTANT FOR THE INCREASE
IN SERVICES DURING THE PANDEMIC
WAS THE REMOVAL OF REGULATORY
AND REIMBURSEMENT ISSUES
ALLOWING FOR CARE ACROSS STATE
LINES IN THE U.S. AND MORE
IMPORTANTLY, TO ALLOW FOR
AUDIO-ONLY VISITS.
THE TERMS TELEHEALTH AND
TELEMEDICINE ARE OFTEN USED
INTERCHANGEABLY, BUT FOR
CLARITY, TELEHEALTH IS A BROAD
TERM WHICH REFERS TO MORE
CLINICAL AS WELL AS NON-CLINICAL
SERVICES SUCH AS PROVIDER
TRAINING, ADMINISTRATIVE
MEETINGS AND CONTINUING MEDICAL
EDUCATION.
ON THE OTHER HAND, TELEMEDICINE
IS A SUBSET OF TELEHEALTH AND
REFERS SPECIFICALLY TO REMOTE
CLINICAL SERVICES.
BEFORE COVID, TELEHEALTH
UTILIZATION VARIED ACROSS
NATIONS AND COUNTRIES.
TECHNOLOGIES AND REGULATIONS
SURROUNDING TELEHEALTH
SIGNIFICANTLY INFLUENCED ITS
USAGE.
FOREIGNERS INCLUDED DEVELOPED
COUNTRIES LIKE THE U.S., YET
INTERINTERESTINGLY ONLY ABOUT -T
USED TELEHEALTH SERVICES IN
2016.
ON THE OTHER HAND, PRECOVID IN
LOW AND MIDDLE INCOME COUNTRIES,
TELEHEALTH WAS MOSTLY
NON-EXISTENT OR IN ITS INFANCY.
WITH THE ONSET OF COVID AS
MENTIONED BEFORE, THERE WAS AN
EXPLOSION OF TELEHEALTH
SERVICES.
IIN THE FIRST QUARTER OF 2020, T
SHOWED 154% INCREASE IN
TELEHEALTH VISITS.
NOW SAID TO HAVE STABILIZED
SOMEWHERE AROUND 38 TIMES HIGHER
THAN LEVELS IN 2019.
IN ONTARIO, CANADA, PRE-COVID
TELEMEDICINE VISITS WERE
REPORTED AT 11 VISITS PER
THOUSAND PATIENTS IN RURAL
AREAS, AND 7 VISITS PER THOUSAND
PATIENTS IN URBAN AREAS.
COMPARE THAT TO POST-COVID,
WHERE VISITS WERE NOW
147 PERCENT THOUSAND AMONG RURAL
PATIENTS, AND 220 VISITS PER
THOUSAND AMONG URBAN DWELLERS.
TELTELEHEALTH USE WA INCREASED %
IN A SURVEY CONDUCTED ACROSS
DIFFERENT COUNTRIES IN THE
MIDDLE EAST AND NORTH AFRICA
REGION.
IN A LITERATURE REVIEW OF
TELEHEALTH SERVICES, 66 WERE
NEWLY ADOPTED INITIATIVES DURING
THE PANDEMIC.
THERE WERE OTHER SUCH REPORTS
HIGHLIGHTING THE GROWTH OF
TELEHEALTH DURING THE PANDEMIC.
INDEED IF WE ACTUALLY LOOK AT A
SCOPE IN REVIEW DONE IN JANUARY
OF JUNE TO 2020, TELEHEALTH WAS
BEING USED WORLDWIDE BUT MOSTLY
IN THE AMERICAS AND IN EUROPE,
MOSTLY HIGH INCOME COUNTRIES,
AND MOST OF THE TELEHEALTH
VISITS WERE FOR CLINICAL CARE OR
FOR FOLLOW-UP.
SICKLE CELL DISEASE IS A CHRONIC
HEREDITARY HEMOGLOBINOPATHY.
LIFETIME MORBIDITY AND DECREASED
SURVIVAL, THEY WERE CONSIDERED A
VULNERABLE POPULATION IF THEY
WERE TO GET COVID INFECTION.
AS SUCH, THIS LED TO THE
IMPLEMENTATION OF THE SECURE
REGISTRY, GLOBAL REGISTRY VERY
EARLY IN THE PANDEMIC AND THIS
HAS SINCE REPORTED GREATER RISK
OF SERIOUS ILLNESS,
HOSPITALIZATION AND DEATH FROM
COVID IN PERSONS WITH DISEASE.
WITH REGARDS TO HEALTHCARE
UTILIZATION, GLOBALLY THERE WAS
A DECLINE IN HEALTHCARE
UTILIZATION DURING THE PANDEMIC,
AND THIS TREND WAS NOTED IN
PERSONS WITH DISEASE.
REPORT FROM A U.S.-BASED
COMMUNITY ORGANIZATION FROM
PEOPLE WITH DISEASE SHOWED THAT
ONLY 35% SOUGHT ER CARE AND 53%
REPORTED MANAGING THEIR PAIN
CRISIS AT HOME DURING THE
PANDEMIC.
A SPECIALTY CENTER IN THE UK
REPORTED APPROXIMATELY 49%
REDUCTION IN PATIENT ADMISSIONS
FOR VASO-OCCLUSIVE CRISES IN THE
FIRST THREE MONTHS OF THE
PANDEMIC.
THEN IF WE LOOK ON TCD SCREEN
SCREENING, THEY REPORTED A 67%
DECLINE IN TCD SCREENING.
WITH REGARD TO TELEMEDICINE,
BEFORE COINDIVIDUALS REPORTS OF
A TELEMEDICINE CLINIC FOR ADULT
PATIENTS INCREASED ACCESS TO
CARE AND SIMILARLY TELEMEDICINE
VISITS ALLOWED FOR CONTACT WITH
SICKLE CELL DISEASE CHILDREN WHO
HAD DEFAULTED FROM CARE IN A
RURAL MEDICALLY UNDERSERVED
AREA.
AFTER COVID, IN ONE REPORT IN
CHILDREN, OUTPATIENT TELEHEALTH
VISITS INCREASED FROM .4%
PREPANDEMIC TO 10.7% IN THE
PANDEMIC.
AND REPORTS OUT OF NIGERIA SHOW
THAT APRIL TO JULY 2020, THERE
WAS A GRADUAL INCREASE IN PHONE
COMMUNICATION WITH PHYSICIANS,
AND 60.8% OF THE PARTICIPANTS
OPTED TO CONTINUE MOBILE
TELEMEDICINE CARE AFTERWARDS.
THE SICKLE CELL UNIT IS A
COMPREHENSIVE CARE CENTER FOR
SICKLE CELL DISEASE.
WE HAVE OVER 10,000 PATIENTS IN
OUR DATABASE.
WE SEE ROUGHLY 2,500 PATIENTS
EACH YEAR FOR ABOUT 9,000
PATIENT VISITS.
OUR SERVICES INCLUDE HEALTH
MAINTENANCE VISITS AND A DAY
WARD TO TREAT ACUTE
COMPLICATIONS.
WE HAD TO DEVISE WAYS TO
SAFELILY VISIT WITH PATIENTS
DURING THE PANDEMIC, AND THIS
LED TO THE IMPLEMENTATION OF
TELEVISITS.
TELEVISITS WERE ESSENTIALLY
TELEPHONE CHECK-INS WITH
PATIENTS WHO WERE MOSTLY ROUTINE
APPOINTMENTS OR FOLLOW-UP VISITS
FOR LAB REVIEW.
AS SUCH, WE SOUGHT TO EXAMINE
THE USE OF TELEHEALTH AS AN
ALTERNATE TOOL FOR THE DELIVERY
OF PARTICULAR HEALTHCARE IN
PERSONS WITH SICKLE CELL DISEASE
A VULNERABLE POPULATION DURING
THE COVID-19 PANDEMIC.
SPECIFICALLY, WE WANTED TO
COMPARE IN TWO PANDEMIC YEARS TO
THE YEAR PRIOR, CLINIC
REGISTRATION NUMBERS, DAYCARE
ADMISSIONS AND IN-PERSON VERSUS
TELEVISITS.
JAMAICA'S FIRST COVID-19 PATIENT
PRESENTED ON MARCH 10, 2020.
AS SUCH, THIS WAS A
RETROSPECTIVE ANALYSIS OF
PATIENT ENCOUNTERS OVER A
THREE-YEAR PERIOD.
YEAR ZERO, PREPANDEMIC, YEAR ONE
AND YEAR TWO DURING THE
PANDEMIC.
THE PATIENT ENCOUNTERS THAT WE
EXAMINED INCLUDED REGISTRATION
NUMBERS, DEFINED AS CLINIC
WALK-INS FOR PHYSICIAN OR
TREATMENT-ONLY VISITS, AND STUDY
VISITS, WHICH WE DEFINED AS
PHYSICIAN TO PATIENT CONSULTS,
EITHER FACE-TO-FACE OR A
TELEVISIT.
ANALYSIS WAS PERFORMED AND
VERSION 16 WAS USED FOR
ANALYSIS.
ETHICS APPROVAL WAS OBTAINED FOR
THE MONA CAMPUS RESEARCH ETHICS
COMMITTEE.
AND OUR RESULTS.
THERE WAS A TOTAL REGISTRATION
NUMBER OF 17,295 PATIENTS.
COMPARED TO YEAR ZERO, NUMBERS
FELL IN YEAR ONE BY 43.8%, AND
IN YEAR TWO, BY 35%.
WHEN WE LOOKED AT MONTHLY
REGISTRATION NUMBERS, OUR LOWEST
REGISTRATION NUMBERS WERE IN
APRIL AND MAY 2020, BUT
REGISTRATION NUMBERS AGAIN FELL
IN SEPTEMBER 2020 AND OCTOB
OCTOBER 2021 DURING THE FIRST
AND THE THIRD WAVES OF THE
PANDEMIC.
WITH REGARDS TO DAY-CARE
ADMISSIONS, THERE WAS A STEADY
DOWNWARD TREND IN YEAR ONE AND
YEAR TWO.
THE TOTAL ADMISSIONS AS WELL AS
FOR BOTH ADULT AND CHILD
ADMISSIONS, HOWEVER, DECLINE WAS
MORE NOTICEABLE WITH CHILD
ADMISSIONS.
WITH REGARDS TO PATIENT NUMBERS,
3,429 PATIENTS HAD A STUDY VISIT
OVER THE THREE-YEAR PERIOD.
40% OF THE PATIENTS WITH STUDY
VISITS WERE SEEN AT LEAST ONCE
IN EACH YEAR, AND 33.5% WERE
SEEN IN ONLY ONE STUDY YEAR.
FOR STUDY VISITS, THERE WERE
21,905 STUDY VISITS RECORDED,
AND THESE OCCURRED IN 3,429
INDIVIDUALS.
MOST WERE ADULT, FEMALE, AND HAD
HBSS GENOTYPE.
STUDY VISITS INCREASED IN YEAR
ONE BY 4.9%, AND IN YEAR TWO BY
1.3% COMPARED TO YEAR ZERO.
MOST OF OUR STUDY VISITS WERE IN
PERSON.
HOWEVER, IN-PERSON VISITS FELL
IN YEAR ONE BY 24%, AND IN YEAR
TWO BY 34.5%.
DURING THE PANDEMIC YEARS,
TELEVISITS ACCOUNTED FOR 31.4%,
ALL STUDY VISITS, AND THERE WAS
AN INCREASE BY 23.1% IN
TELEVISITS BETWEEN YEAR ONE AND
YEAR TWO.
STUDY VISITS INCREASED IN ADULTS
IN THE PANDEMIC YEARS BY 30.1%
IN YEAR ONE, AND 8.2% IN YEAR
TWO.
HOWEVER, THEY FELL IN THE
CHILDREN IN THE PANDEMIC YEARS
BY 3.2% AND 6.2% IN YEAR ONE AND
YEAR TWO RESPECTIVELY.
BOTH TELEVISITS, HOWEVER,
INCREASED IN ADULTS AND CHILDREN
IN THE PANDEMIC YEARS.
ALL VISITS WERE NOT CODED AND
THIS REFERS TO THE FINAL
DIAGNOSIS GIVEN AT THE END OF
THE VISIT.
IN THE PANDEMIC YEARS, 96.7% OF
THE VISITS WERE CODED, 60.4% OF
THE TELEVISITS WERE CODED.
AND WHEN WE LOOK ON THE CODED
TELEVISITS, 78.3% WERE
ASSOCIATED WITH A WELL VISIT,
17.6% WITH THE HYDROXYUREA
VISIT, AND 2.8% WERE ASSOCIATED
WITH A PAIN VISIT.
SO LOOKING AT THIS, WE CAN SEE
THAT SICKLE CELL UNIT
REGISTRATION NUMBERS FELL IN THE
PANDEMIC YEARS, BUT THEY DID
SHOW AN INCREASE IN THE SECOND
YEAR OF THE PANDEMIC.
AND THIS IS ACTUALLY KEEPING
WITH OTHER STUDIES THAT HAVE
SHOWN A REBOUND IN HEALTHCARE
UTILIZATION AFTER THE EARLY
PANDEMIC PERIOD.
THE DECLINING NUMBERS FOR OUR
DAY WARD WAS CONSISTENT WITH ER
TRENDS.
OUR NUMBERS, HOWEVER, MAY HAVE
BEEN AMPLIFIED BY A DIRECT
REFERRAL TO HOSPITAL POLICY FOR
PATIENTS WHO AT TRIAGE HAVE A
HIGH RISK ASSESSMENT FOR COVID
AS OUR CLINIC ORIENTATION DID
NOT ALLOW US TO SEPARATE THESE
INDIVIDUALS FROM OTHER PATIENTS,
SO WE DID NOT WANT TO PUT OUR
OTHER PATIENTS AT RISK.
OUR STUDY ALSO SHOWED AN
INCREASE IN STUDY VISITS DURING
THE PANDEMIC YEARS, AND THIS WAS
MOSTLY DUE TO THE ADDITION OF
TELEVISITS, WHICH ARE CODED FOR
31.4% OF STUDY VISITS IN THE
PANDEMIC YEARS, AND BOTH
CAREGIVERS AND PATIENTS WITH
SICKLE CELL DISEASE IN A NUMBER
OF STUDIES HAVE SHOWN HIGH
SATISFACTION WITH USE OF
TELEHEALTH IN HEALTHCARE
DELIVERY.
DESPITE AN INCREASE IN STUDY
VISITS, THE NUMBER OF PERSONS
UTILIZING SERVICES FELL.
PATIENT BARRIERS, INCLUDING
TELECOMMUNICATION CHALLENGES,
LIMITED KNOWLEDGE ABOUT
TELEHEALTH, MAY HAVE AFFECTED
ACCESS AND USE.
ALMOST A THIRD OF ALL PATIENTS
WERE ONLY SEEN IN ONE STUDY
YEAR, AND THIS IS A LITTLE BIT
UNEXPECTED AS MOST OLDER
CHILDREN AND ADULTS WOULD BE
EXPECTED TO HAVE AT LEAST ONE TO
TWO ROUTINE HEALTH MAINTENANCE
CHECKS AND YOUNGER CHILDREN UP
TO FOUR ROUTINE HEALTH
MAINTENANCE CHECKS EACH YEAR.
WE LOST CONTACT WITH 17% OF
PATIENTS WHO WERE ONLY SEEN IN
THE PREPANDEMIC YEARS DESPITE
TELEVISITS.
ON THE OTHER HAND, ALMOST A
QUARTER OF OUR PATIENTS WERE
ONLY SEEN IN THE PANDEMIC YEARS,
AND SO IT IS PROBABLE THAT
TELEVISITS ALLOWED US TO REACH
OUT TO SOME PERSONS WHO HAD
DEFAULTED FROM CARE.
SO IF WE LOOK AHEAD, IT SEEMS
CLEAR THAT THERE IS A ROLE FOR
TELEMEDICINE IN SICKLE CELL
DISEASE HEALTHCARE.
IT HAS BEEN SHOWN TO BE FEASIBLE
AND ACCEPTABLE BY BOTH PATIENTS
AND HEALTHCARE PROVIDERS,
HOWEVER, AS PROVIDERS, WE WILL
NEED TO ASSESS OUR DELIVERY
SYSTEMS, LEGISLATION, INSURANCE,
ET CETERA, THAT'S GOING TO BE
NEEDED TO FACILITATE
TELEMEDICINE, AND DEFINITELY
FURTHER RESEARCH IS NEEDED ON
HEALTH OUTCOMES AND EXPERIENCES
WITH TELEMEDICINE.
THESE ARE MY REFERENCES.
THANK YOU, EVERYBODY, AND I HOPE
YOU ENJOY THE REST OF YOUR
CONFERENCE.
GOODBYE.
>> THANK YOU, DR. KING.
DR. KING IS ON ZOOM WITH US, SO
IF THERE ARE ANY QUESTIONS HERE
IN THE AUDIENCE, SHE WILL BE
ABLE TO TAKE THEM LIVE.
I DON'T SEE ANY QUESTIONS IN THE
CHAT.
FOR THOSE WHO ARE ON VIRTUALLY,
YOU HAVE TO RELEASE THEM TO LIVE
FEEDBACK, SO THEN WE CAN
TRANSFER THEM AND CHAT AND
PRESENT THEM TO DR. KING FOR
YOU.
DR. KING, I HAVE A QUESTION.
IS THERE ANY ABILITY TO LOOK AT
YOUR DATA TO SEE IF THERE ARE
ANY PREDICTORS FOR
CHARACTERISTICS IN YOUR PATIENT
POPULATION THAT WOULD IDENTIFY
THOSE WHO ARE A BETTER FIT FOR
TELEHEALTH, BECAUSE WE DID
SEE -- WE DID HAVE DIVERSE
EXPERIENCES AT OUR CENTER WHERE
SOME PATIENTS WERE POORLY
CONNECTED, THEN BECAME FURTHER
NON-ADHERENT AFTER TELEHEALTH
IMPLEMENTATION.
>> WE HAVEN'T ACTUALLY LOOKED AT
THAT.
WE DO KNOW THAT FOR MOBILE AND
CONNECTIVITY IS ALWAYS A PROBLEM
IN JAMAICA.
WE ALSO ARE CULTURALLY -- YOU
KNOW, A NUMBER OF OUR PATIENTS,
UNLESS THEY ACTUALLY COME TO THE
DOCTOR TO HAVE THEIR CHEST
SOUNDED, AS WE WOULD SAY, THEY
WOULDN'T FEEL THAT THEY WOULD
HAVE HAD AN ADEQUATE VISIT BY A
DOCTOR.
AND SO WE WOULD PROBABLY NEED TO
EXAMINE A LITTLE BIT MORE TO SEE
THE DIFFERENCES IN THE
CHARACTERISTICS OF THE PATIENTS
WHO WERE MORE COMPLIANT WITH THE
TELEHEALTH VISITS AND THOSE WHO
WEREN'T.
>> THANK YOU SO MUCH.
APPRECIATE T TH IT.
THAT WAS WONDERFUL.
ALL RIGHT, WE WILL MOVE ON TO
OUR NEXT TALK, WHICH IS CURRENT
AND EMERGING THERAPEUTIC AGENTS
IN SICKLE CELL DISEASE.
THIS TALK WILL BE PRESENTED BY
DR. CHARLES QUINN, WHO IS ALSO A
PEDIATRIC PROVIDER, PEDIATRIC
HEMATOLOGIST, PROFESSOR OF
PEDIATRICS AT CINCINNATI
CHILDREN'S HOSPITAL MEDICAL
CENTER.
HE'S THE MEDICAL DIRECTOR OF THE
PEDIATRIC SICKLE CELL PROGRAM
AND CO-DIRECTOR OF THE
ERYTHROCYTE DIAGNOSTIC
LABORATORY, AND WE LOOK FORWARD
TO HEARING FROM HIM ABOUT
CURRENT THERAPEUTICS.
>> THANK YOU FOR THE INVITATION.
EARLIER WE WERE REVIEWING OUR
JAMAICAN CONNECTION.
SADLY I'M NOT FROM JAMAICA BUT
THE LAST TIME I WAS IN JAMAICA,
I LOST A TOOTH.
MY DENTIST TELLS ME IT WAS A
CONGENITAL ABNORMALITY OF FUSION
OF THE ENAMEL.
I LIKE TO TELL PEOPLE I WAS IN A
BAR FIGHT.
IT'S MUCH MORE INTERESTING.
ALL RIGHT.
SO CURRENT -- I HOPE I DON'T
LOSE ANOTHER TOOTH AT THIS SCIF
CONFERENCE HERE.
CURRENT AND EMERGING THERAPEUTIC
AGENTS IN SICKLE CELL DISEASE.
I'M GOING TO FOCUS HERE ON THE
FDA-APPROVED THERAPIES FOR
SICKLE CELL DISEASE, AND RIGHT
AT THE BEGINNING, AT THE OUTSET,
THIS IS GOING TO BE A U.S. OR A
HIGH RESOURCE ENVIRONMENT
CENTRIC VIEW AND CENTRIC TALK.
THESE ARE THE -- SO YOU MIGHT
ASK, WELL, ARE THESE EMERGING
THERAPIES IN THE U.S.?
AND, WELL, THESE ARE THE CURRENT
AGENTS, BUT I THINK THEY'RE
RESPECTIVE AND THEIR ADDITIVE
ROLES ARE STILL EMERGING.
WHEREAS ANOTHER REG WILL TRI
RREGULATORYREGIONS OR COUNTRIESE
TRULY EMERGING AS THEY MAY
BECOME AVAILABLE SOON.
SO WE'LL TALK ABOUT THESE FOUR.
I HAVE RECEIVED RESEARCH FUNDING
FOR SOME PKPT WORK FOR
L-GLUTAMINE FROM THE
MANUFACTURER OF ENDARI.
ALL RIGHT.
SO EVERYTHING WITH SICKLE CELL
DISEASE AND SICKLE CELL ANEMIA
IN PARTICULAR START WITH SICKLE
HEMOGLOBIN, AND A MUTATION IS
HERE, AS YOU ALL KNOW IT, AND
WHAT THAT MUTATION LEADS TO IS
POLYMERIZATION OF HEMOGLOBIN IN
THE DEOOXYGENATED STATE.
YOU KNOW THE RED BLOOD CELL IS
PACKED FULL OF HEMOGLOBIN, AND
IT SHOULD BE, EVEN THOUGH THE
RED BLOOD CELLS TIGHTLY PACKED
WITH HEMOGLOBIN, IT SHOULD BE
FREELY SOLUBLE, BUT BECAUSE OF
THIS MUTATION, THEIR
INTERMOLECULAR CONTEXT UPON
DEOXYGENATION THAT LEAD TO A
CYCLIC AND REVERSIBLE PROCESS
THAT DAMAGES THE MEMBRANE HERE.
AND ONE THING TO POINT OUT HERE
IS THAT ALL PATHOPHYSIOLOGY IN
SICKLE CELL DISEASE IS
DOWNSTREAM FROM THE ABNORMAL
HEMOGLOBIN AND ITS
POLYMERIZATION, SO NIL THERAPY
THAT YOU DEVISE FOR SICKLE CELL,
THE CLOSER IT IS TO THIS CAUSE
OF POLYMERIZATION, THE BETTER
THE THERAPY IT WILL LIKELY TO
BE.
NOW WE'LL TALK ABOUT THE FOUR
AGENTS THAT ARE FDA-APPROVED.
THE FIRST IS HYDROXYUREA.
THIS IS THE ONE THAT'S BEEN
KNOWN ABOUT FOR THE LONGEST TIME
THAT WE'VE BEEN USING IT FOR
DECADES, REALLY.
PROOF OF PRINCIPLE STUDIES IN
SICKLE CELL IN THE 80s, IT WAS
FDA-APPROVED FOR ADULTS 18 AND
OLDER IN 1998, BUT ONLY UNTIL
2017 WAS IT FDA-APPROVED IN KIDS
GREATER THAN EQUAL TO 2 YEARS OF
AGE.
NOW, ITS MECHANISM OF ACTION,
YOU LOOK IT UP, YOU MAYBE
LEARNED IT AS A MEDICAL STUDENT,
IS A RIBONUCLEOTIDE REDUCTASE
INHIBITOR.
HOW EXACTLY THIS MECHANISM OF
ACTION LEADS TO THE LABORATORY
CLINICAL EFFECTS IS A BIT OF A
BLACK BOX AND THAT DESERVES A
LOT OF RESEARCH IN AND OF
ITSELF, BUT WHEN WE GIVE
HYDROXYUREA, WE INDUCE FETAL
HEMOGLOBIN, AND AS YOU REMEMBER,
DOWN HERE, HEMOGLOBIN F IS
INCORPORATED INTO THAT FIBER AS
IT'S GROWING AND INHIBITS
FURTHER POLYMERIZATION SO YOU
CAN THINK OF IT AS A CHAIN
TERMINATOR.
SO IT INDUCES FETAL HEMOGLOBIN,
AND THEN OTHER LABORATORY
EFFECTS INCREASED MCV, INCREASED
CELLULAR HYDRATION, DECREASED
WHITE COUNT, PLATELET COUNT, ALL
THESE OTHER THINGS.
AND THIS, AS YOU KNOW, IS A
MEDICINE THAT'S TAKEN ORALLY AND
ONCE A DAY.
SO IT DOES HAVE PLEIOTROPIC
EFFECTS BUT MOST OF THE EFFECTS,
THE PREDOMINANT EFFECTS RELATE
TO INDUCTION OF FETAL
HEMOGLOBIN.
AND I LIKE TO SHOW THIS SLIDE
BECAUSE THIS WAS IN THE STUDY
HALL IN ASH A COUPLE OF YEARS
AGO.
I WALKED BY GENE THERAPY BOOT
STUDY RATIONALE, FETAL
HEMOGLOBIN IS THE STRONGEST
PREDICTOR OF SICKLE CELL DISEASE
CLINICAL COURSE.
IT SAID HERE AVERAGE HEMOGLOBIN
F LEVELS AFTER TREATMENT, 9 TO
18%.
I SAID THAT'S INTERESTING.
AND DOWN HERE, IT SAYS THAT THE
CURATIVE OR FUNCTIONAL
LIQUEURTIVE NEW TREATMENTS AIM
FOR GREATER THAN 30%.
SO CLEARLY THAT'S NOT
HYDROXYUREA, RIGHT?
SO THIS IS AN OLD DRUG THAT
NEEDS REPLACEMENT, OR IS IT?
AND THE ANSWER IS YES IF YOU
STILL USE IT LIKE IT'S THE 19 TE
1990s.
SO IT'S AN OLD DRUG BUT WE CAN
USE NEW -- WE CAN ACHIEVE MUCH
GREATER HEMOGLOBIN F INDUCTION
IN CHILDREN AND MAINTAIN THIS
OVER MANY YEARS, UP TO CLOSE TO
A DECADE NOW FOR SOME OF THESE.
SO THE AVERAGE F THAT WE'RE
GETTING IS 20 TO 40%, SO REALLY
HAD TO EXTRAPOLATE OFF THIS
THING HERE.
AND HOW DO WE DO THAT?
WE HAVE TO START EARLY.
AND I'M TALKING 6 TO 9 MONTHS OF
AGE, PRESYMPTOMATIC OR PREMOST
SYMPTOMS, RIGHT, AND THEN WE
HAVE TO USE THE OPTIMAL DOSE,
AND WE AT LEAST DO IT BY
PK-GUIDED THERAPY, BECAUSE
EVERYBODY IS DIFFERENT.
EVERYBODY METABOLIZES, HANDLES
DRUG DIFFERENTLY, ANY DRUG, AND
STARTING EVERYBODY AT A STANDARD
PER KIE L KILO DOSE YOU'RE LIKET
OPTIMIZING THERAPY FOR ANYBODY.
WE DON'T SLOWLY WORK UP TO THE
M.T.V., BEGIN AT THE PREDICTED
M.T.V. AND MAINTAIN THAT OPTIMAL
DOSE OVER TIME.
AND THAT MAINTENANCE IS ACTUALLY
WHAT TAKES A LOT OF EFFORT.
FREQUENT DOSE ADJUSTMENTS IN
GROWING KIDS.
SO EVERY VISIT, EVERY OTHER
VISIT YOU'RE TWEAKING THE
HYDROXYUREA DOSE.
IF YOU DON'T DO THAT, THEY'LL
QUICKLY OUTGROW THEIR DOSE AND
DEVELOP PROBLEMS AS A
CONSEQUENCE OF THAT.
AND THAT REQUIRES A SYSTEM AND A
LOT OF RESOURCES ESPECIALLY
AROUND PATIENT ADHERENCE AND
SUPPORT TO MAKE THAT HAPPEN, AND
NOT ONLY DOES THAT REQUIRE A LOT
OF -- A BIG SYSTEM AND A LOT OF
RESOURCES.
THAT'S GOT TO BE MAINTAINED OVER
THE LIFE OF THE INDIVIDUAL IF
YOU'RE GOING TO CONTINUE USING
HYDROXYUREA IN AN OPTIMAL WAY.
AND SO WE CAN USE WITH PK-GUIDED
THERAPY AND STARTING EARLY, WE
CAN GET REALLY ROBUST INDUCTION
OF FETAL HEMOGLOBIN, YOU KNOW,
AVERAGE IS -- THIS IS AN EXAMPLE
PATIENT, WHEN YOU'RE BORN YOU
HAVE PREDOM NABTLY FETAL
HEMOGLOBIN, IT DECLINES.
THIS IS WHEN YOU START
HYDROXYUREA HERE.
MAYBE EVEN EARLIER.
YOU DON'T WANT TO JUST PREVENT
THE DECLINE, BUT YOU WANT TO
BRING IT RIGHT BACK UP, RIGHT?
AND IF WE DO THAT EARLY, AT THE
RIGHT DOSE, WE CAN ACHIEVE NEAR
PAN CELLULAR F CELL HEMOIMLOA
BIN F EXPRESSION, SO THIS IS AN
EXAMPLE PATIENT WITH 98% F
CELLS.
SO ESSENTIALLY PAN-CELLULAR.
OF COURSE NOT EVERYBODY IS
PAN-CELLULAR.
ABOUT 50% OF THIS COHORT THAT
WE'RE FOLLOWING HAS PAN CELLULAR
OR NEAR PAN CELLULAR FETAL
HEMOGLOBIN EXPRESSION.
OBVIOUSLY THERE'S SOME THAT HAVE
LESSER RESPONSES FOR VARIOUS
REASONS, AND THIS IS WHAT
TROUBLES ALL OF US IN THE FIELD,
RIGHT?
AND SO AGAIN, WHAT DO WE DO?
THIS IS WHAT WE HAVE.
YOU HAVE TO START EARLY AND YOU
HAVE TO OPTIMIZE THE DOSE AND
THEN YOU HAVE TO MAINTAIN THAT
OPTIMAL DOSE OVER TIME, RIGHT?
AND NOT ONLY DO YOU HAVE TO LOOK
AT IT IN THE INDIVIDUAL BUT YOU
HAVE TO HAVE A SYSTEM-WIDE OR A
POPULATION-BASED METHOD OF
TRACKING THIS.
SO HERE WE CAN SEE PERCENT FETAL
HEMOGLOBIN, 40% OVER EIGHT
YEARS, 40% OVER EIGHT YEARS, AND
SO THAT'S GREAT WHEN YOU HAVE
ONE OF THESE INDIVIDUAL PATIENTS
THAT DOES EXTREMELY WELL.
WHAT ABOUT FOR THE ENTIRE
POPULATION?
SO THIS IS -- WE'RE MEASURING
FETAL HEMOGLOBIN AS A QI END
POINT, RIGHT, FOR SICKLE CELL
PATIENTS, SICKLE CELL ANEMIA WHO
ARE ON HYDROXYUREA.
AND THESE ARE THE PROPORTION OF
PATIENTS IN BLACK HERE WHOSE
FETAL HEMOGLOBIN IS GREATER THAN
20%.
SO 70% OF THE ENTIRE POPULATION,
UP TO AGE 21, HAS A FETAL
HEMOGLOBIN GREATER THAN 20%.
THAT USED TO BE REALLY GOOD.
I DON'T THINK IT'S THAT GOOD
ANYMORE, SO WE REALLY NEED TO
IMPROVE THAT, SO ABOUT 40% OF
OUR POPULATION IS AT LEAST 30%.
ONCE WE GET THE F TO 30%, WE'RE
GETTING ABOUT 80% F CELLS, SO
WE'VE GOT LOTS MORE PROTECTION
OF ERYTHROCYTE FROM SICKLING.
SO START EARLY, OPTIMIZE THE
KODOSE AND MAINTAIN IT OVER TIM.
SO I THINK I'M PREACHING TO THE
CHOIR HERE IN THAT RESPECT.
BUT WHAT DO WE KNOW ABOUT
HYDROXYUREA?
IT TEE CREASES PAINFUL EPISODES,
DECREASES CHEST SYNDROME.
DECREASES STROKE, BOTH PRIMARY
AND SECONDARY, DECREASES THE
FREQUENCY OF PLA TRANSFUSIONS,
INCREASES HEMOGLOBIN, INCREASES
HEMOGLOBIN F, IMPROVES RHEOLOGY,
IMPROVES QUALITY OF LIFE, PRO
LONGS LIFE AND YEARLY COST OF
ABOUT $2,000 PER YEAR OF LIFE.
SO LET'S TALK ABOUT PATIENTS AND
HOW THEY FIT INTO THAT PARADIGM.
WHEN WE'RE THINKING ABOUT THAT,
GOING BACK TO THAT QUESTION
ABOUT HYDROXYUREA, IS IT THE OLD
DRUG THAT NEEDS REPLACEMENT OR
IS IT THE THING THAT'S CLOSEST
TO THE CURE CURRENTLY THAT
SHOULD BE MET OR EXCEEDED BY NEW
THERAPIES?
I THINK THE ANSWER IS YES, I
THINK IT DOES NEED REPLACEMENT
BY SOMETHING BETTER BUT BE SURE
THAT WE REPLACE IT WITH
SOMETHING BETTER.
SO L-GLUTAMINE, EARLY STUDIES
WERE DONE IN THE 1970s, BUT IT
WASN'T UNTIL 2017 THAT IT WAS
APPROVED FOR PEOPLE WITH SICKLE
CELL DISEASE AGE 5 AND UP.
AND THERE'S A LOT OF TEXT HERE,
BUT HOW IS GLUTAMINE IMPORTANT
TO THE BODY?
THAT'S SORT OF LIKE ASKING HOW
IS GLUCOSE IMPORTANT TO THE
BODY, OR HOW IS PHOSPHOROUS
IMPORTANT TO THE BODY?
THIS IS ONE OF THE MOST ABUNDANT
AMINO ACIDS IN THE BODY, AND SO
IT DOES A LOT OF THINGS.
BUT AS A HEMATOLOGIST, PROBABLY
TOO NARROW OF A VIEW THINKING
ABOUT HOW GLUTAMINE MIGHT WORK.
IT IS A PRECURSOR FOR THE
SYNTHESIS OF GLUTATHIONE, GSH,
ADENINE AND ARGININE.
BUT ITS MECHANISM OF ACTION IS
REALLY NOT WELL CHARACTERIZED.
IT'S THOUGHT TO BE MAINLY AROUND
REDUCED OXIDATIVE STRESS BECAUSE
OF THIS.
IT'S AN ORAL POWDER, YOU TAKE IT
TWICE DAILY.
SO HYDROXYUREA IS ONCE DAILY.
HERE A POWDER YOU HAVE TO MIX IN
SOMETHING OR SPREAD ON
SOMETHING, PEOPLE DON'T LIKE IT.
IT'S NOT ANYTHING THAT IS TWICE
A DAY IS NOT AS GOOD AS ONCE A
DAY IN TERMS OF PALATABILITY AND
ACCEPTABILITY.
AND WHAT DOES DO, AT LEAST IN
TWO OR THREE CLINICAL TRIALS,
SHOWED DECREASED FREQUENCY OF
PAINFUL EPISODES AND PAINFUL
SICKLE CELL-RELATED ACUTE
EVENTS.
BUT IT DIDN'T DO MUCH OF THE
OTHER THINGS THAT HYDROXYUREA
DOES HERE.
SO THIS IS JUST SOME HISTORY
HERE OF SS ERYTHROCYTES AND
GLUTAMINE, AND REALLY I
EXPLAINED THIS IN THE PREVIOUS
SLIDE, BUT THE THEORY IS THAT
THE INCREASED NAD TURNOVER DUE
TO ONGOING OXIDATIVE INJURY WITH
A COMPENSATORY INCREASE -- TO
SUPPORT NAD SYNTHESIS, AND THAT
FORMED THE BASIS FOR STUDIES,
HERE'S ANOTHER WAY OF THINKING
ABOUT IT HERE, ERYTHROCYTE,
OXIDATIVE STRESS FROM THE
ERYTHROCYTE DUE TO SICKLE
HEMOGLOBIN AND THE DOWNSTREAM
CONSEQUENCES OF POLYMERIZATION,
AND WHAT CAN QUENCH OXIDATIVE
STRESS NADPH GLUTE THIGH YOAN
AND A PRECURSOR IS L-GLUTAMINE.
SO THAT MAKES A NICE STORY FOR
THE HEMATOLOGIST BUT REALLY THE
MECHANISM OF ACTION IS UNCLEAR
SO WE'VE BEEN DOING SOME -- AND
I TOOK OUT SOME OF THE STUDIES
THAT WE'VE DONE FOR THIS
PARTICULAR TALK MAKING IT A BIT
MORE CLINICAL LOOKING AT THE
PK-PD ASSOCIATIONS WITH
GLUTAMINE, BUT WHAT WE FOUND, IF
WE NOT JUST -- WE DON'T JUST
LOOK AT HOW MUCH L-GLUTAMINE
YOUR DOSE IS, LIKE 30 MG, YOU
KNOW, WHAT -- IT'S LIKE HOW
MUCH -- WHAT WAS THE MAXIMUM
CONCENTRATION?
WHAT WAS THE AREA UNDER THE
CURVE THAT YOU ACHIEVED IN YOUR
BLOODSTREAM WHEN YOU GOT GLUED
GLEUT MEAN?
GLUTAMINE?
SO WE FOUND HIGHER C MAX OR
AUCs -- DECREASED POINT OF
SICKLING BY OXYGEN GRADIENT
CYTOMETRY, INCREASED ARGININE
BIOAVAILABILITY AND HAD SOME
OTHER EFFECTS BUT INTERESTINGLY
IT MADE BLOOD MORE VISCOUS AND
HAD SOME OTHER THINGS LIKE
HEMOGLOBIN, HEMATOCRIT WENT UP
BUT THAT COULD MAKE VISCOSITY
HIGHER UNLESS THERE'S AN
OTHERWISE BENEFICIAL IMPROVEMENT
IN RHEOLOGY.
SO I THINK THIS IS WHY THE
BENEFICIAL EFFECTS OF GLUTAMINE
ARE HARD TO TEASE OUT,
ESPECIALLY IN A CLINICAL TRIAL
THAT'S JUST FOCUSED ON
VASO-OCCLUSIVE CRISIS, ONE
THING, AND SICKLE CELL AFFECTS
SO MANY DIFFERENT THINGS, AND I
THINK DIFFERENT PEOPLE ARE
DIFFERENT, AND ARE GOING TO
RESPOND DIFFERENTLY TO THIS
MEDICATION.
SO WE DON'T KNOW MUCH ABOUT IT.
IT SEEMS TO DECREASE PAIN.
SO -- BUT NOT SO MUCH IN THE WAY
OF STRONG EVIDENCE FOR CHEST
SYNDROME WITH STROKE, IT DOESN'T
DO ANYTHING WITH TRANSFUSIONS,
HEMOGLOBIN, HEMOGLOBIN F.
POSSIBLY IT IMPROVES RHEOLOGY
BUT THAT'S SOME OF THE
PHARMACODYNAMIC STUDIES THAT
WE'RE DOING, AND IT'S MORE
EX-PIN SIEVE.
IT MAY IMPROVE QUALITY OF LIFE
BUT NOBODY HAS DONE THAT STUDY
AND PROVIDED DIRECT EVIDENCE FOR
THAT.
SAME THING WITH PROLONGATION OF
LIFE.
SO HYDROXYUREA AND L-GLUTAMINE.
NOW, WE'LL DO CRIZANLIZUMAB
NEXT.
I THINK IT WELL-KNOWN TO THIS
GROUP.
WE STARTED LEARNING ABOUT
ADHESIONS AND SELECTINS IN
SICKLE CELL DISEASE IN THE
1990s.
THIS WAS APPROVED IN 2019 FOR 16
AND UP, AND AS YOU KNOW,
HUMANIZED MONOCLONAL ANTIBODY
AGAINST P SELECTINS -- NOT ONLY
TO EACH OTHER BUT TO THE
ENDOTHELIAL SURFACE AS WELL, AND
SO THIS CAUSES STASIS AND THEN
SECONDARY TO THAT, BECAUSE OF
DEOXYGENATION, A VASOOCCLUSION,
AND THEN ISCHEMIA REPERFUSION
INJURY.
SO IF WE GIVE P-SELECTIN, IT CAN
INHIBIT SOME OF THOSE
INTERACTIONS AND DECREASE
VASOOCCLUSION.
AND SO LABORATORY EFFECTS,
THERE'S NOT MUCH THAT HAPPENS IN
THE BLOOD COUNTS THAT YOU CAN
MEASURE OR SEE, AND IT'S GIVEN
BY AN IV INFUSION MONTHLY.
SO AGAIN, LIKE L-GLUTAMINE,
DECREASES PAIN.
THIS ONE IS GIVEN IV, IT'S GIVEN
MONTHLY EXCEPT FOR THE FIRST
THREE DOSES, WHICH ARE TWO WEEKS
APART.
NOW THE PROBLEM IS, I DON'T KNOW
HOW MUCH LONGER WE'LL BE TALKING
ABOUT THIS.
HOPEFULLY -- WE DO HAVE PATIENT
ON ALL OF THESE THERAPIES THAT
I'M TALKING ABOUT WITH -- SO
JUST BECAUSE I DON'T POINT OUT
SOMETHING IT DOESN'T MEAN I
DON'T THINK IT'S WORTHWHILE.
NO STATISTICALLY SIGNIFICANT
DIFFERENCE BETWEEN CRIZ AND
PLACEBO, SO THIS REGULATORY FATE
IN THE U.S. AND THE E.U. IS
PROBABLY GOING TO BE DIFFERENT,
SO I DON'T KNOW WHERE THAT'S
GOING TO END UP.
BUT RIGHT NOW, WE HAVE IT, AND I
DO USE IT AND IT SEEMS TO BE
HELPFUL FOR A SMALL POPULATION
OF PATIENTS THAT GET THAT FAR.
SO WHAT DOES DO?
DECREASES PAINFUL EPISODES, YES.
LESS INFORMATION ABOUT CHEST
SYNDROME, STROKE, THAT SORT OF
THING.
NO EFFECTS ON YOUR BLOOD COUNTS.
AND IT'S A LOT MORE EXPENSIVE,
RIGHT, SO $100,000.
NOW LET'S ADD IN ANOTHER THING.
SO HERE, COMPARISON OF EFFECTS
OF THESE DIFFERENT AGENTS ON VOC
RATE, AND THIS WAS PUBLISHED IN
2021.
AND THE MSH TRIAL, L-GLUTAMINE
PHASE THREE STUDIES, THE SUSTAIN
TRIAL.
YOU CAN SEE EACH OF THESE
DECREASED ANNUALIZED CRISIS RATE
BY ABOUT 45%, PRETTY EQUIVALENT,
SO THESE SHOULD BE
INTERCHANGEABLE.
WELL, I THINK IF YOU'RE USING
HYDROXYUREA AS IT WAS IN 1995,
THAT THAT'S UND UNDERTREATMENT.
BECAUSE WE CAN SEE MUCH MORE
DRAMATIC EFFECTS NOW.
IF YOU OPTIMIZE THE DOSE FOR
EACH INDIVIDUAL AND MAINTAIN
THAT OVER TIME.
SO THIS IS COMPARING 90s DATA
TO 2015, 2020 DATA, AND WE USE
HYDROXYUREA DIFFERENTLY.
WE MAY USE CRIZ AND GLUTAMINE
AND VOX DIFFERENTLY IN 2040, AND
WE'LL HAVE TO M KOL BACK AND COD
REMIND OURSELVES ABOUT THAT AS
WELL.
SO EACH CAN DECREASE VOC RATE
AND SUPERFICIALLY IT SEEMS LIKE
THEY'RE RELATIVELY EQUIVALENT,
BUT REMEMBER THAT THE MSH TRIAL
WAS RELATIVE UNDER TREATMENT.
COMPARED TO HOW WE USE IT IN
HEALTHY CHILDREN WITH SICKLE
CELL ANEMIA STARTED EARLY TODAY.
ALL RIGHT.
SO VOX IS THE OTHER TREATMENT,
WE KNEW THERE WAS SOMETHING
DIFFERENT ABOUT HEMOGLOBIN
OXYGEN AFFINITY IN SICKLE CELL
DISEASE STARTING IN THE 1950s,
AND THIS WAS AN AGENT THAT WAS
APPROVED IN 2019 AND THEN
REDUCED AGE OF INDICATION IN 20
WEN ONE.
SO WHAT IS IT?
IF YOU READ THE PACKAGE INSERT,
IT SAYS THIS IS A FIRST IN CLASS
POLYMERIZATION INHIBITOR.
WELL, IT'S NOT REALLY, PER SE.
IT DECREASES THE FORMATION OF
THE THING THAT POLYMERIZES.
SO IT'S UPSTREAM OF THAT.
IT INCREASES HEMOGLOBIN OXYGEN
AFFINITY, SO IT STABILIZES THE
ALLOSTERIC R STATE.
WHAT DOES DO, LABORATORY
EFFECTS?
IT DOES INCREASE YOUR
HEMOGLOBIN, DECREASES RETICS AND
SURROGATE MARKERS OF HEMOLYSIS,
SO IT DOES SEEM TO HAVE SOME
EFFECT ON IMPROVING YOUR BLOOD
COUNTS.
THIS IS NICE, IT'S TAKEN ORALLY
AND ONCE DAILY, AND THEN THE
CLINICAL EFFECTS, DECREASED
ANEMIA.
SO HERE, THIS WAS DIFFERENT THAN
THE CRIZ AND THE ENDARI.
HERE WE HAVE SOMETHING TARGETING
THE ANEMIA.
AND AGAIN, REMEMBER, IT COVAL
COVALENTLY MINDS BIENDZ THE --
IT'S NOT A RAPID ON/OFF SORT OF
THING.
I JUST WANTED TO BRING UP SOME
OLD STUDIES HERE.
EVERYBODY TALKS ABOUT THIS AS IF
THERE IS SOME INTRINSICALLY
ABNORMAL DECREASED OXYGEN
AFFINITY OF HEMOGLOBIN S.
THAT'S NOT TRUE.
THE OXYGEN AFFINITY OF S IS THE
SAME AT A, AND THAT COMES FROM
THE ORIGINAL REPORT.
IT'S JUST THAT THOSE HEMOGLOBIN
MOLECULES ARE IN A RED CELL THAT
HAS MORE 2, 3-DPG, SO THAT WILL
DECREASE OXYGEN AFFINITY,
INCREASE THE FRACTION OF
DEOXYHEMOGLOBIN.
SO YOU COULD EITHER DECREASE THE
PRODUCTION OF 2, 3-DPG OR YOU
COULD INTRINSICALLY MAKE
HEMOGLOBIN A OR S HAVE A HIGHER
AFFINITY FOR OXYGEN.
VOXELOTOR DOES THE LATTER.
OTHER EMERGING BUT NOT APPROVED
STUDIES, AGENTS LIKE PK
ACTIVATORS ACTUALLY DECREASE THE
PRODUCTION OF 2, 3-DPG AND MAY
ACHIEVE THE SAME EFFECT
DIFFERENTLY.
SO THIS IS JUST SHOWING YOU THE
EFFECT OF VOXELOTOR ON
HEMOGLOBIN OXYGEN AFFINITY.
HERE'S PO2, SO AS YOU DIAL UP
THE AMOUNT OF OXYGEN IN THE
SOLUTION, HEMOGLOBIN SHOULD BE
INCREASINGLY SATURATED, AND SO
ANYTHING THAT SHIFTS TO THE LEFT
INCREASES OXYGEN AFFINITY,
RIGHT?
SO IT ONLY TAKES A LITTLE BIT OF
OXYGEN TO GET HIGHER SATURATION.
AND SO THIS IS NICELY MOD LATES
HEMOGLOBIN OXYGEN AFFINITY.
IT DOES IT IN A DIFFERENT WAY
THAN 2, 3-DPG, WHICH AFFECT ALL
THE HEMOGLOBIN MOLECULES.
HERE VOXELOTOR MODIFIES ABOUT A
THIRD, 30% OR SO OF HEMOGLOBIN
MOLECULES, MAKES THEM VERY HIGH
OXYGEN AFFINITY, BUT THE REST
ARE UNMODIFIED.
SO IT'S DIFFERENT, AND I TOOK
OUT A SLIDE TO ILLUSTRATE THAT
FOR TIME, BUT AGAIN, VOXELOTOR,
IT'S COVALENT HEMOGLOBIN
MODIFICATION, ALLOSTERIC R STATE
STABILIZER.
SO WHAT DOES DO?
IT INCREASES OXYGEN AFFINITY.
SO IF YOU CAN'T DEOXYGENATE,
THEN YOU'LL HAVE DECREASED
SICKLING.
OF COURSE YOU ALSO NEED
DEOXYGENATION TO LIVE, RIGHT?
YOU NEED OXYGEN TO LIVE SO YOU
NEED TO DEOXYGENATE, SO IT'S
THAT BALANCE.
SO YOU DON'T WANT TO INCREASE
THE OXYGEN AFFINITY TOO FAR TO
DECREASE HEMOGLOBIN OXYGEN
UNLOADING, BUT YOU WOULD LIKE TO
DECREASE SICKLING, IMPROVE THE
HEMOGLOBIN OXYGEN DELIVERY,
IMPROVE RHEOLOGY AND WHERE DOES
THE BALANCE LIE IN THIS
PARTICULAR ILLUSTRATION, THIS
WAS FROM A STUDY ILLUSTRATING
THE EFFECTS OF WHAT WAS SEEN IN
THAT PARTICULAR STUDY, AND I'M
NOT SUGGESTING THAT VOXELOTOR
ALWAYS DECREASES OXYGEN DELIVERY
TO TISSUES, BUT THIS IS THE
BALANCE, AND IT'S PROBABLY
DIFFERENT IN DIFFERENT PEOPLE,
RIGHT?
AND LIKE HYDROXYUREA, YOU SHOULD
PROBABLY DO PK AND OPTIMIZATION
STUDIES AND FIGURE OUT WHAT IS
THE BEST DOSE, NOT EVERYBODY
SHOULD TAKE THE SAME DOSE.
AND THIS IS ANOTHER WAY OF
LOOKING AT IT.
SO PEOPLE IN VOXELOTOR STUDY HAD
AUGUAUGMENTATION IN THEIR
HEMOGLOBIN, SOME VERY
DRAMATICALLY.
SOME, HEMOGLOBIN DECREASED, AND
SOME ARE IN THE MIDDLE HERE, SO
THERE ARE PROBABLY SOME THAT DO
HAVE A NET GAIN IN OXYGEN
DELIVERY CAPACITY AND
IMPROVEMENT IN BLOOD FLOW, BUT
THERE ARE PROBABLY SOME THAT
HAVE A NET LOSS, AND DO THEY
HAVE AN IMPROVEMENT IN BLOOD
FLOW?
DON'T KNOW.
AND SO THIS IS AN AREA THAT
NEEDS TO BE STUDIED.
SO IF WE PUT THESE TOGETHER
HERE, WE CAN SEE THAT VOXELOTOR
DOESN'T DO MUCH OTHER THAN
INCREASE YOUR HEMOGLOBIN AS FAR
AS WE KNOW IT CURRENTLY.
THERE MAY BE MORE BUT IT HASN'T
BEEN SHOWN.
IN RANDOMIZED TRIALS
YET AND IT EXPENSIVE LIKE ANY OF
THE NEWER AGENTS.
SO WHEN WE THINK ABOUT THESE
EMERGING THERAPIES, SO TO SPEAK,
THE FACTORS TO CONSIDER IN MY
MIND, AT LEAST I'M LUCKY TO LIVE
AND PRACTICE IN A CENTER THAT
HAS THESE OPTIONS, WE CAN THINK
ABOUT ALL OF THESE -- THIS CAN
BE DONE FOR SICKLE CELL DISEASE
BROADLY, NOT JUST SICKLE CELL
ANEMIA, BUT MOST OF THE DATA ARE
FROM SICKLE CELL ANEMIA, SO WHEN
WE HAVE THESE AGENTS, WE CAN
THINK ABOUT HOW OLD THE PATIENT
IS, SO THE PATIENT'S AGE,
PATIENT PREFERENCE, DO THEY WANT
TO TAKE SOMETHING ORAL OR IV, IS
IT BURDENSOME TO TAKE SOMETHING
DAILY OR TWICE DAILY, AND THEN
WHAT ARE THE THERAPEUTIC
BENEFITS YOU'RE TRYING TO
ACHIEVE?
AND THAT MIGHT INFORM WHAT
THERAPY YOU'RE GOING TO ADD ON
TO THE BACKBONE OF THERAPY.
AND THEN COST, MONEY AND
INFRASTRUCTURE, YOU'LL NEED AN
INFUSION CENTER, FOR EXAMPLE.
SO ANOTHER WAY -- MY VIEW IS
THAT OPTIMIZED HYDROXYUREA
SHOULD BE THE BACKBONE OF
THERAPY TO WHICH OTHER PAIGHTS
ARE ADDED SO WE CAN PREVENT ALL
THOSE THINGS THAT WE'VE BEEN
TALKING ABOUT TODAY AS MUCH AS
POSSIBLE, RATHER THAN TREAT THEM
AFTER THEY HAPPEN.
AND THIS TAKES A SYSTEM, SO WE
START HYDROXYUREA EARLY, AND
THERE'S A PSYCHOSOCIAL GROUP
THAT HELPS US WITH HESITATION,
SHARED DECISION-MAKING,
ADHERENCE, AND TO THAT,
DEPENDING ON THE CLINICAL
CIRCUMSTANCES, IF THERE'S PAIN,
WE CAN TALK ABOUT DO YOU WANT TO
ADD CRIZ OR GLUTAMINE, WE HAD
VOXELOTOR OR SOME COMBINATION
OF -- WE HAVEN'T GOTTEN TO A
COMBINATION OF THREE YET, BUT
I'M SURE WE WILL, BUT THIS DOES
TAKE EFFORT AND TIME, AND SO IN
SUMMARY THEN, I THINK THAT MAYBE
I HAVEN'T SHOWED YOU ALL THE
DATA, BUT USING PK GUIDED
HYDROXYUREA INITIATED MTD IN
EARLY CHILDHOOD, WE CAN INDUCE
PAN-CELLULAR IN A LARGE VOLUME
OF PATIENTS WITH SICKLE CELL AND
WE'RE FOLLOWING THIS COHORT OVER
TIME.
WHAT WE DO IS WE ADD THOSE OTHER
THERAPIES THAT ARE AVAILABLE TO
OPTIMIZE THERAPY, IF THERE'S
PREDOMINENCE OF PAIN DESPITE
HYDROXYUREA, ADD ON CRIZ OR L
GLUED MEAN OR THE OTHER.
BUT YOU KNOW, IN THE AGE OF
GENETIC AND CURATIVE THERAPIES
THAT ARE HERE AND NOW, SO YOU
MIGHT THINK WHY ARE WE BOTHERING
WITH THIS?
WELL, PATIENT ARE ALIVE NOW AND
WE NEED TO IMPROVE AND MAINTAIN
THEIR CURRENT HEALTH AND WE WANT
TO KEEP THEM AS HEALTHY AS
POSSIBLE FOR THEIR CURRENT AND
FUTURE ITERATIONS OF GENETIC AND
CURATIVE THERAPY.
I'M TELLING PATIENTS PROBABLY IN
YOUR LIFETIME YOU'RE GOING TO
GET A GENETIC THERAPY BUT WITH
HWEHAVE TO KEEP YOU HEALTHY BECE
ANY ORGAN DAMAGE YOU SUSTAIN
UNTIL THEN, THAT'S NOT GOING TO
GET BETTER.
SO EVEN THOUGH GENETIC AND
CURATIVE THERAPIES, UNIVERSAL
THERAPIES ARE ON THE HORIZON,
YOU STILL HAVE TO KEEP THE
PATIENTS VERY HEALTHY, AS MUCH
AS POSSIBLE NOW.
AND I'LL STOP THERE.
THANKS.
[APPLAUSE]
>> THANK YOU SO MUCH.
I HAVE ONE QUESTION IN THE CHAT
THAT I'D LIKE TO BRING UP TO
YOU.
THIS IS FROM TIFFANY CHEN.
SHE SAYS, I ALSO SHARE YOUR
ENTHUSIASM FOR HYDROXYUREA AT
OPTIMALLY TITRATED DOSES.
DO YOU ANTICIPATE IN THE MODERN
ERA THAT PEDIATRICS SCD PATIENTS
STARTED AT A VERY YOUNG AGE ON
PK-GUIDED DOSING WILL BE ABLE TO
MAINTAIN OPTIMAL -- DOSES FOR
MAXIMAL F INDUCTION INTO
ADULTHOOD, AND IF NOT, WHAT DO
YOU THINK ARE THE SPECIFIC
BARRIERS?
>> YEAH, SO THE ANSWER TO THE
FIRST PART, IS I THINK IT CAN,
BUT WE'RE STILL FOLLOWING -- YOU
KNOW, WE'VE ONLY FOLLOWED
PATIENTS ABOUT 10 YEARS NOW,
SO -- AND FOR THOSE THAT
CONTINUE TO TAKE IT, AND FOR
THOSE IN WHOM WE'RE ABLE TO KEEP
UP WITH THE DOA IT S DOSE, IT SE
EFFECTIVE.
BUT THERE MAY BE SOME
DEVELOPMENTAL -- BUT AT LEAST
WE'RE KEEPING YOU HEALTHY UNTIL
YOU CAN GET YOUR CURATIVE
THERAPY HOPEFULLY IN YOUR
PATIENT'S LIFETIME.
I THINK THE BIGGEST BARRIER THAT
WE HAVE IS LIKE ANY CHRONIC
DISEASE IS ADHERENCE.
SO IF YOU HAVE A SICKLE CELL
TREATMENT CENTER, YOU HAVE TO DO
SOMETHING TO SUPPORT PATIENT
ADHERENCE, AND WE HAVE SOME
PSYCHOLOGISTS THAT ARE
INTEGRATED INTO OUR TEAM, AND
YES, THEY DO MENTAL HEALTH, BUT
ONE OF THE MAIN THINGS THEY DO
IS ADHERENCE SUPPORT.
SO I THINK THAT IS THE BIGGEST
BARRIER.
OH, THAT'S GOOD.
I DIDN'T WANT ANY QUESTIONS.
I CAN HEAR YOU.
>> -- SO EARLY AND ESPECIALLY
WITH WHAT LYDIA HAS JUST
PRESENTED ABOUT DIMINISHED
OVARIAN RESERVE.
-- USING THE NEUTROPENIA KIND
OF -- JUST USING THE MCV.
SO YOU START THE CHILDREN AS
YOUNG AS SIX MONTHS OR NINE
MONTHS, DO YOU NOT HAVE ANY
CONCERN?
>> WELL, WE DO HAVE CONCERNS,
AND WE'RE MONITORING THEM
CLOSELY PROSPECTIVELY AND IN
DETAILED ORGAN ASSESSMENTS,
EVERYTHING FROM MRIs OF THE
HEART AND BRAIN AND THAT SORT OF
THING, SO YES, BUT AS YOU
PROBABLY -- THESE KIDS ARE
HEALTHIER.
THEY DON'T HAVE GROWTH DELAY.
WE'RE NOT -- WE HAVE OBESITY, WE
HAVE THE PROBLEM OF PREGNANCY
AND PREVENTING PREGNANCIES, AN
AND -- WHAT WAS THE SECOND PART
OF YOUR QUESTION THERE?
>> HOW DO YOU SLEEP --
>> OH, SO YOU TAKE A
CONSERVATIVE ENVIRONMENT, ONCE
YOU SEE AN EFFECT, THEN CAN YOU
GO AHEAD AND STOP, WELL, I MEAN,
LET'S JUST APPLY THAT TO ASTHMA.
SO IF YOU GIVE A BRONCHODILATOR,
YOU CAN KEEP SOMEBODY OUT OF THE
ICU AND GETTING THEM -- PREVENT
THEM FROM BEING INTUBATED, BUT
IS THAT THE MAIN GOAL, JUST TO
PREVENT THEM FROM BEING
INTUBATED, OR DO YOU REALLY WANT
TO IMPROVE THEIR PULMONARY
HEALTH BROADLY?
WHAT ABOUT DIABETES?
IF YOU GIVE THEM JUST ENOUGH
INSULIN TO PREVENT THEM FROM
HAVING DKA, SEU YOU'VE MADE AN
EFFECT BUT YOU WOULDN'T STOP
THERE, RIGHT, BECAUSE YOU KNOW
DIABETES IS A LIFELONG SEVERE
DISEASE THAT CAUSES ORGAN
DAMAGE, SO YOU WANT TO TITRATE
THAT TO GET MAXIMAL -- WE DON'T
WANT TO GO BEYOND MAXIMAL
CLINICAL BENEFIT, BUT WE WANT TO
TITRATE TO CLINICAL BENEFIT.
AND THE THINGS THAT WE MEASURE
ARE OVERT COMPLICATIONS.
>> THERE IS A CRUCIAL
DIFFERENCE.
DIABETES, YOU HAVE THE GLUCOSE
LEVELS TO HELP YOU.
BLOOD PRESSURE, YOU HAVE THE
NUMBERS TO INDICATE.
HYDROXYUREA, ALL OF THESE ARE
JUST NUMBERS.
YOU'RE TREATING THE PATIENT.
>> RIGHT, WE'RE TREATING THE
PATIENT, AND WE KNOW --
>> AND ACTUALLY THE GREEK STUDY,
THEY DON'T USE MTD AND THEY ALSO
PROLONGED THE LIVES.
>> OH, YEAH, THEY'LL GO UP, BUT
NOT IN TO PAN-CELLULAR
INDUCTION.
I MEAN, WE DON'T -- WE'RE NOT
PUTTING KIDS ON CHRONIC
TRANSFUSIONS ANYMORE.
THE CHRONIC TRANSFUSION
POPULATION IS SHRINKING.
WE DON'T SEE -- WE DON'T EVEN
SEE ABNORMAL TCDs ANYMORE.
I MEAN, EVERYTHING -- AND THE
INPATIENT POPULATION IS
SHRINKING.
WE HAD A SEQUESTRATION EVENT THE
OTHER DAY AND EVERYBODY WAS
LIKE, WHAT IS THAT?
I WAS LIKE, WELL, THIS IS HOW IT
USED TO BE.
SO WE'RE JUST NOT SEEING WHAT WE
DID BEFORE.
SO I THINK THAT OVERALL, I MEAN,
WHAT WE'RE MEASURING AND WHAT
YOU SEE IS JUST THE TIP OF THE
ICEBERG.
BECAUSE THERE'S CHRONIC
INSIDIOUS CUMULATIVE
IRREVERSIBLE ORGAN DAMAGE
HAPPENING EVERY DAY, WE CAN'T
MEASURE THAT DIRECTLY, EASILY,
WE CAN WITH SOME MECHANISMS BUT
YOU CAN'T PUT SOMEBODY IN THE
SCANNER AND GIVE THEM GADOLINIUM
ALL THE TIME.
SO WE'RE HOPING FOR A HEALTHIER
POPULATION THAT AREN'T A
AZOOSPERMIC.
AND LYDIA, YOU WERE HOPING FOR
SOME ARGUMENTS AND SOME
PUNCHING.
>> NO, NO.
I THINK WHAT YOU'RE SAYING IS
VERY IMPORTANT BECAUSE I GET A
LOT OF QUESTIONS IN MY TALKS
ABOUT THE IMMENSE AMOUNT OF
ANXIETY THAT MY DATA PROVOKES,
PARTICULARLY FOR PEDIATRIC
PRACTITIONERS, AND I THINK THAT
PART OF THE ANSWER TO THAT
ANXIETY IS THAT WE HAVE TO HELP
PEOPLE IMAGINE HEALTHY CHILD
HOODS FROM CHILDREN WITH SICKLE
CELL DISEASE, AND I THINK THAT
YOUR DATA HELPS WITH THAT
FAILURE TO IMAGINE.
SO THAT WAS THE FIRST THING I
WANTED TO ACKNOWLEDGE.
YOU MENTIONED THAT YOU'RE
FOLLOWING END ORGAN ASSESSMENTS,
SO I WONDERED IF WERE YOU
INCLUDING IN POST PUBESCENT
GIRLS ANTIMA LAYE ANTIMA --
>> YES, AND SEMEN ANALYSIS FOR
THOSE WHO WILL BE WILLING TO
HELP US WITH THAT INFORMATION.
>> I HAD ANOTHER QUESTION WHICH
WAS YOUR GROUP HAS PUBLISHED
THAT YOU INCORPORATE FERTILITY
RISK COUNSELING INTO YOUR
HYDROXYUREA PRESCRIBING PARADIGM
BUT YOU'VE NEVER DESCRIBED THE
COMPONENTS OF THAT COUNSELING.
COULD YOU TALK A LITTLE BIT
ABOUT -- COULD YOU MODEL THAT
CONVERSATION FOR US?
BECAUSE I THINK IT'S A SOURCE OF
IMMENSE ANXIETY FOR MANY OF THE
PEOPLE I MEET OUT HERE IN SICKLE
CELL LAND.
>> YEAH, I THINK IT AN EXCELLENT
AND IMPORTANT QUESTION.
I'M NOT SURE I CAN DO JUSTICE TO
IT, BUT THOSE CONVERSATIONS,
IT'S NOT A MONOLITHIC
CONVERSATION.
BUT SINCE I SEE PATIENTS FROM
BIRTH UNTIL 21, LITTLE BITS OF
IT HAPPEN OVER TIME.
AND WE ADD IN BITS OF THAT.
I THINK WE'RE STILL TRYING TO
BUILD IN AS WELL AS YOU HAVE,
THINGS LIKE FERTILITY
ASSESSMENTS AND OVARIAN RESERVE
ASSESSMENTS, I DON'T HAVE A
SYSTEMATIC WAY OF DOING THAT NOW
OTHER THAN JUST TALKING ABOUT IT
OVER TIME WITH PATIENTS.
AND AS AN ANECDOTE, YOU HAVE TO
BE VERY CAREFUL ABOUT THE WAY
YOU TALK ABOUT IT WITH PATIENTS,
BECAUSE WHEN WE HAVE -- ONE OF
THE NURSE PRACTITIONERS TOLD ME
SHE WAS TALKING TO HER TEEN
PATIENT AND SHE SAID, NOW YOU
KNOW WHEN YOU'RE ON HYDROXYUREA,
YOU CAN'T GET PREGNANT WHILE
YOU'RE ON HYDROXYUREA.
LIKE -- BUT WHEN SHE CAME BACK
PREGNANT, SHE'S LIKE, I THOUGHT
YOU SAID I COULDN'T GET
PREGNANT.
SO CAN'T, SHOULDN'T, WE DO HAVE
TO BE VERY CAREFUL.
SO I DON'T HAVE A GREAT ANSWER
TO YOUR QUESTION OTHER THAN IT
ORGANIC AND IT HAPPENS OVER THE
SPACE OF 21 YEARS AND I THINK WE
CAN LEARN FROM YOU AND WHAT
YOU'RE DOING TO IMPROVE OUR
PROCESSES.
BUT REMEMBER YOU DO HAVE TO GROW
UP TO BE ABLE TO HAVE A CHILD,
YOU HAVE TO BE HEALTHY ENOUGH TO
HAVE A CHILD, AND HOPEFULLY YOU
CAN BE HEALTHY ENOUGH THAT YOU
CAN HAVE A SAFE PREGNANCY.
>> THANK YOU.
>> CAN I HAVE A QUESTION,
PLEASE?
>> I THINK WE'LL HAVE TO ASK DR.
>> OKAY, OKAY.
>> THANK YOU, THOUGH.
AND I DO AGREE, THAT'S A VERY
DIFFICULT POSITION TO BE IN.
WE'LL MOVE ON.
ALL RIGHT.
I HAVE MANY THOUGHTS AS WELL BUT
WE'LL MOVE ON.
OUR NEXT SPEAKER WILL BE JOINING
US AS A PRERECORDED TALK.
WE HAVE DR. WALLY SMITH, WHO
WILL BE PRESENTING TO US REAL
WORLD USE OF CURRENT
THERAPEUTICS IN SICKLE CELL
DISEASE.
THIS WILL GIVE US A VERY
DIFFERENT PERSPECTIVE FROM
DR. QUINN'S, I IMAGINE.
DR. SMITH IS THE FLORENCE NEIL
COOPER SMITH PROFESSOR OF SICKLE
CELL DISEASE AT VIRGINIA
COMMONWEALTH UNIVERSITY.
HE HAS CARED FOR PATIENTS WITH
SICKLE CELL DISEASE FOR OVER 40
YEARS, IS BEST KNOWN FOR HIS
PISCES STUDY, AND I LOOK FORWARD
TO HEARING HIS PERSPECTIVE.
>> THANK YOU FOR THE OPPORTUNITY
TO TALK TODAY ABOUT REAL WORLD
USE OF CURRENT THERAPIES FOR
SICKLE CELL DISEASE.
THESE ARE MY CONFLICTS, AND --
CONFLICTS OF INTEREST.
I'M GOING TO TRY TO ANSWER
SEVERAL COMMON QUESTIONS,
FREQUENTLY ASKED QUESTIONS
REGARDING REAL WORLD USE OF
THERAPIES FOR SICKLE CELL
DISEASE TODAY.
AND WARN YOU IN ADVANCE THAT WE
DON'T HAVE GOOD DATA TO ANSWER A
NUMBER OF THESE QUESTIONS.
THERE'S FEW PUBLISHED STUDIES
ABOUT MANY OF THESE QUESTIONS.
MANY OF THE DATABASES THAT WE
MIGHT WANT TO USE TO ANSWER
THESE QUESTIONS SUCH AS MARKET
SCAN AND THE PHARMA DATABASE ARE
PROPRIETARY AND THERE ARE FEW
PHASE FOUR STUDIES FOR
INDIVIDUAL AGENTS.
FURTHER, THERE'S VERY LITTLE
INFORMATION ABOUT ADHERENCE TO
ANYTHING EXCEPT HYDROXYUREA.
IN FACT, ONLY A THIRD OF AFRICAN
AMERICANS POLLED ARE AWARE THAT
SICKLE CELL DISEASE
DISPROPORTIONATELY AFFECTS
PEOPLE OF AFRICAN DESCENT.
EXOWB S SO THIS GOES ALONG WITH
THE LITTLE ATTENTION OFTEN BEING
PAID TO ISSUES RELATED TO REAL
WORLD USE OF THERAPEUTICS IN
SICKLE CELL DISEASE.
HERE'S THE FIRST QUESTION I'LL
TRY TO ANSWER.
HOW ARE YOU OR HOW ARE WE, AS
PEDIATRICIANS AND ADULT
PROVIDERS, DOING WITH ROUTINE
VACCINATIONS AND PROPHYLACTIC
PENICILLIN AND STROKE
PREVENTION?
WHICH EVERYBODY WOULD AGREE IS
COST-EFFECTIVE AND IMPORTANT
THERAPY.
ITS NET BENEFIT TO SOCIETY PER
THE U.S. PREVENTIVE HEALTH
SERVICES TASK FORCE, IT'S
MANDATED IN ALL 50 STATES.
AND IT'S RECOMMENDED WORLDWIDE
IN COUNTRIES SUCH AS THE UNITED
STATES, ENGLAND, FRANCE, SPAIN,
BELGIUM AND THE NETHERLANDS.
THE BRITISH NATIONAL HEALTH
SERVICE AND THE WORLD HEALTH
ORGANIZATION HAVE GUIDELINES
PUBLISHED ON THIS.
IN THE UNITED STATES, THE
MORTALITY DUE TO SICKLE CELL
DISEASE IS RAPIDLY DECLINING,
LARGELY ATTRIBUTED TO NEWBORN
SCREENING.
SIMILARLY IN A JAMAICAN COHORT,
THERE'S BEEN INCREASED SURVIVAL
OVER TIME, AGAIN, ATTRIBUTED TO
NEWBORN SCREENING.
AND DESPITE THIS, THERE IS NOT
THE USE OF THE FOLLOW-UP TESTS
SUCH AS PROPHYLACTIC PENICILLIN
OR, IN THIS CASE, TRANSCRANIAL
DOPPLER SCREENING.
FEWER THAN HALF OF THE CHILDREN
RECEIVED ANNUAL TRANSCRANIAL
DOPPLER SCREENING IN ONE MARKET
STUDY.
THOTHESE ARE PEOPLE WITH PRIVATE
INSURANCE SO PAYMENT SHOULD NOT
BE A PROBLEM.
SO PEOPLE ARE MISSING OUT ON
CHRONIC TRANSFUSION AND STROKE
PREVENTION IN A LARGE NUMBER OF
CASES WHEN IT'S VERY CLEAR THAT
THAT IS SOMETHING WE SHOULD BE
DOING.
THERE'S ALSO OVERALL
UNDERUTILIZATION OF NEEDED
THERAPIES AMONG PATIENTS WITH
SICKLE CELL DISEASE.
THIS IS A STUDY OF PATIENTS WITH
CEREBROVASCULAR DISEASE, BUT YOU
CAN IMAGINE SIMILAR STUDIES OF
PATIENTS WITHOUT SCREEN ROW
VASCULAR SCREEN CEREBROVASCULARW
UTILIZATION OF THINGS SUCH AS
BLOOD TRANSFUSION, TCD,
HYDROXYUREA, ET CETERA.
IT IS POSSIBLE TO IMPROVE
QUALITY IN PATIENTS WITH SICKLE
CELL DISEASE.
THIS IS THE QUALITY OF
TRANSITION SUPPORT, AND HERE
WE'RE SHOWING INCREASES IN THE
14ST3P-UP SITES.
THIS WAS A STUDY OF PEER
MENTORING TO IMPROVE THE
TRANSITION QUALITY IN
ADOLESCENTS AND YOUNG ADULTS.
AND YOU CAN SEE HERE DRASTIC
IMPROVEMENTS IN BOTH PEDIATRIC
AND ADULT QUALITY IMPROVEMENT
SCORES OVER THE COURSE OF THE
STUDY.
WITH OR WITHOUT PEER MENTORING.
SO IT IS POSSIBLE TO IMPROVE
THESE THINGS.
AND WE HAVE THE NATIONAL
ALLIANCE OF SICKLE CELL CENTERS,
WHOSE GOAL IS TO IMPROVE THE
QUALITY OF CARE FOR PATIENTS
WITH SICKLE CELL DISEASE TO SET
STANDARDS OF CARE, COME UP WITH
CONSENSUS RECOMMENDATIONS ON
WHAT IS HIGH QUALITY CARE, AND
QUALITY INDICATORS AND THEN
MEASURE OURSELVES AGAINST THOSE
QUALITY INDICATORS.
BUT WE ARE VERY, VERY EARLY IN
THAT PROCESS.
NEXT QUESTION, HOW DO YOU
PRESCRIBE HYDROXYUREA?
DO YOU USE THE MAXIMUM TOLERATED
APPROACH OR DO YOU USE A FIRM
FIXED DOSE?
AND DOES IT MATTER WHAT SETTING
IN WHICH YOU'RE ASKING THAT
QUESTION?
LOW RESOURCE SETTING OR A RURAL
PRACTICE SETTING VERSUS A HIGH
RESOURCE SETTING OR AN URBAN
SICKLE CELL CENTER WITH WELL
STAFFED AND HIGHLY RESOURCED
PROARS.
PROVIDPROVIDER.
THIS HAS BEEN HIGHLIGHTED IN A
RECENT ARTICLE BY CHARLES QUINN
IN BLOOD.
HERE'S THE DATA.
MOST OF YOU ARE AWARE THAT
RUSSELL -- HAS BEEN INTERESTED
IN MTD USE IN HYDROXYUREA EVEN
IN LOW RESOURCE SETTINGS, AND HE
STUDIED PATIENTS USING 15 TO
20 MILLIGRAMS PER KILOGRAM PER
DAY FOR SIX MONTHS AND THEN
ESCALATED THEM, FOUND THAT THIS
WAS FEASIBLE TO DO, FOUND VERY
LITTLE DOSE LIMITING TOXICITY
AND REDUCED DEATH AND THIS WAS
IMPORTANT ENOUGH TO BE PUBLISHED
IN THE NEW ENGLAND JOURNAL.
IN CONTRAST, HERE IS A STUDY BY
MIKE DEBAUD AND OTHERS IN ONE
SUB-SAHARAN AFRICAN COUNTRY
WHICH SHOWED THAT THERE WAS NO
DIFFERENCE IN MAIN OUTCOMES
BETWEEN 10 MILLIGRAMS AND
20 MILLIGRAMS PER KILO PER DAY
OF HYDROXYUREA IN A FIXED ORAL
DOSE.
THE CONCLUSION WAS THAT
10 MILLIGRAMS PER KILOGRAM PER
DAY OF HYDROXYUREA IS THE
MINIMUM KNOWN EFFICACIOUS DOSE
FOR STROKE PRESE PREVENTION IN S
PARTICULAR STUDY AND THEY
ACTUALLY STOPPED THE TRIAL.
LATELY, THERE'S BEEN A STUDY BY
AMBROSE AND OTHERS USING
HYDROXYUREA AT 20 MILLIGRAMS PER
DAY TO THE MAXIMUM TOLERATED
DOSE IN ORDER TO SEE WHAT THAT
DOES TO THE TRANSCRANIAL DOPPLER
VELOCITY.
AND THE FINDING WAS THAT IT
DECREASED, DECREASED FROM -- TO
149 AFTER BEGINNING THE STUDY,
VERSUS 182 AND BASELINE.
THEY'RE GIVING HYDROXYUREA AT
THE MAXIMUM TOLERATED DOSE IN
RESPONSE TO THE TRANSCRANIAL
DOPPLER READING.
SO YOU CAN KIND OF PAY YOUR
MONEY AND TAKE YOUR CHOICE ABOUT
WHAT YOU SHOULD DO.
CLEARLY A MINIMUM DOSE MIGHT BE
AN EFFECTIVE STRATEGY IN THE
APPROPRIATE SETTING.
BUT ESCALATION TO MAXIMUM POLL
TOLERATED DOSE IS NOT ASSOCIATED
WITH TOXICITIES AND MAY BE AS
EFFECTIVE OR MORE EFFECTIVE.
WHAT DO YOU DO TO MAKE PEOPLE
TAKE THEIR HYDROXYUREA?
AND THAT'S A BIG PROBLEM IN THE
UNITED STATES.
HOW DO YOU MONITOR THIS, HOW
OFTEN SHOULD YOU MONITOR THIS.
THERE'S MANY, MANY BARRIERS.
PHYSICIANS ARE NOT PRESCRIBING
HYDROXYUREA OFTEN THE WAY THAT
THEY SHOULD BE.
THERE ARE DOUBTS BOTH IN THE
PHYSICIAN'S MIND AND IN THE
PATIENT'S MINDS ABOUT
HYDROXYUREA EFFECTIVENESS.
PATIENTS DON'T FEEL ANYTHING
WHEN YOU GIVE THEM HYDROXYUREA
AT FIRST SO THEY DOUBT ITS
EFFECTIVENESS.
THE PATIENTS HAVE APPREHENSION
ON THE OTHER HAND ABOUT THE
BLACK BOX WARNINGS ON THE
LABELS.
ABOUT ADVERSE EFFECTS.
ABOUT CONCERNS FOR INFERTILITY
AND THE NEED TO USE
CONTRACEPTIVES IN ORDER TO NOT
GET PREGNANT, AND OF COURSE THEY
DON'T ADHERE FOR LONG PERIODS OF
TIME WHEN THEY DON'T SEE BIG
SUBJECTIVE CHANGES.
THE STATES ARE NOT INVESTING ANY
MONEY IN THIS THE WAY WE INVEST
IN PROPHYLACTIC PENICILLIN AND
NEWBORN SCREENING.
AND THE NUMBER OF PATIENTS WHO
ARE ADULTS IS NOT FOLLOWED BY
MOST STATES IN THE UNITED
STATES, SO WE DON'T EVEN KNOW
HOW MANY ADULTS HAVE SICKLE CELL
DISEASE IN MOST STATES, ALTHOUGH
WE ESTIMATE BASED ON THE CLAIMS
DATA THAT TWO THIRDS OF
AMERICANS WHO HAVE SICKLE CELL
DISEASE ARE ADULTS.
WHAT WE DO KNOW IS THAT IF YOU
TAKE HYDROXYUREA BETTER, YOU
FEEL BETTER.
YOU HAVE BETTER RELATED QUALITY
OF LIFE SCORES, MORE PAIN
IMPACT, LESS FATIGUE, AND THIS
WAS SHOWN AS EARLY AS THE
MULTICENTER STUDY FOR
HYDROXYUREA BUT THIS IS AN
ARTICLE PUBLISHED IN 2022.
IN INDIVIDUALS WITH SICKLE CELL
DISEASE FROM 12 DIFFERENT
STUDIES.
WE DON'T HAVE SIMILAR STUDIES TO
EVALUATE ADHERENCE WITH
L-GLUTAMINE, VOXELOTOR OR
CRIZANLIZUMAB TO MATCH UP WITH
THIS.
WE ALSO KNOW THAT IT IS
DIFFICULT TO FIND GOOD DATA ON
TECHNIQUES TO IMPROVE
HYDROXYUREA ADHERENCE.
BASICALLY THE RESULT OF THIS
SYSTEMATIC REVIEW WAS THAT MORE
STUDIES ON HYDROXYUREA ADHERENCE
ARE NEEDED.
AND THAT FEW STUDIES TESTED
ADHERENCE OTHER THAN BEHAVIORAL
CHANGE.
IF YOU LOOK AT THE FEW STUDIES
THAT ARE THERE TO TRY TO IMPROVE
ADHERENCE, YOU CAN SEE THAT
YOUNG ADULTS ACTUALLY HAVE
SIGNIFICANTLY HIGHER HYDROXYUREA
ADHERENCE COMPARED TO CHILDREN
IN ADOLESCENCE, KIND OF
CONTRA -- COUNTERINTUITIVE TO
WHAT I WOULD HAVE EXPECTED.
AND THEN PATIENTS WITH LOWER
HYDROXYUREA ADHERENCE AND
CHRONIC PAIN HAD INCREASED
HEALTHCARE UTILIZATION SIMILAR
TO WHAT WE WOULD HAVE EXPECTED.
NO ASSOCIATIONS WITH GENDER,
SOCIOECONOMIC STATUS, DISTANCE
FROM CARE, OR HYDROXYUREA
DURATION.
HERE IS A SCALE, IF YOU WANTED
TO TRY TO MEASURE ADHERENCE THAT
HAS RECENTLY BEEN PUBLISHED
SUGGESTING A WAY TO MORE EASILY
MEASURE ADHERENCE IS CALLED THE
HYDROXYUREA EVALUATION OF
ADHERENCE FOR LIFE SCALE,
ACTUALLY CAME UPON IT IN
PREPARATION TO GIVE THIS TALK.
WAS NOT AWARE THAT IT EXISTED.
AS YOU CAN SEE, THERE'S ABOUT
20-SOME ITEMS, THERE'S EIGHT
SUBSCALES WITH THREE ITEMS EACH,
DOSE, REMEMBER, PLAN, COST,
UNDERSTAND, EFFECTIVENESS,
LABORATORY AND PHARMACY THIS
DOES REQUIRE PERMISSION TO USE,
SO PLEASE CONTACT THE AUTHORS IF
YOU WOULD LIKE TO USE THIS.
THE FIRST AUTHOR'S NAME IS
JANSON.
IF YOU GET SOPHISTICATED, YOU
CAN USE VIDEO DIRECTLY OBSERVE
THERAPY, OR YOU CAN USE
ELECTRONIC PILL MONITORING, AND
MEDICATION ADMINISTRATION
RECORDS TO MEASURE ADHERENCE.
WITH HYDROXYUREA.
AND OF COURSE YOU CAN USE THE
INDIRECT METHODS, WE ALL ARE
AWARE.
-- VOLUME AND THE FETAL
HEMOGLOBIN, BUT THOSE ARE KIND
OF INDIRECT AS BEHAVIORALLY
ORIENTED MEASURES.
HERE IN THIS STUDY, HIGHER
HYDROXYUREA EXPOSURE WAS OF
COURSE ASSOCIATED WITH IMPROVED
HEMATOLOGIC PARAMETERS.
AND THE NOTE IS THE STUDY WAS
BEING DONE IN THE HIGH INCOME
SETTING, SUGGESTING THAT IN LOW
INCOME SETTINGS, THESE METHODS
MAY NOT BE AVAILABLE OR USEFUL.
WE CHOSE TO USE COMMUNITY HEALTH
WORKERS TO TRY TO IMPROVE
HYDROXYUREA ADHERENCE.
OUR CLINIC IS IN A RELATIVELY
LOW INCOME, URBAN MEDICAL CARE
SYSTEM, AND WE WERE AWARE THAT
COMMUNITY HEALTH WORKERS WORK
ONE-ON-ONE WITH INDIVIDUALS WITH
MANY DISEASES TO IMPROVE HEALTH
OUTCOMES, SUCH AS DIABETES AND
CONGESTIVE HEART FAILURE.
AND THERE ARE MANY, MANY
MILLIONS OF THESE PEOPLE AND YOU
CAN SEE SOME OF THEM HERE.
THEY MAY BE TRAINED AS NURSES
BUT WE WERE PARTICULARLY
INTERESTED IN PEER LATE HEALTH H
PROVIDERS SO WE WENT WITH
NON-TRAINED LAY PEOPLE.
WE STUDIED THIS UNDER THE GUISE
OF A RANDOMIZED CONTROL TRIAL,
CALLED ENHANCING USE OF
HYDROXYUREA IN SICKLE CELL
DISEASE USING PATIENT
NAVIGATORS.
WE RENAMED THE STUDY SHIP HU.
WE HAD TWO HYPOTHESES.
THE SECOND HAD TO DO WITH
GETTING PATIENTS INTO CLINIC,
BUT OUR SECOND HYPOTHESIS WAS
THAT HYDROXYUREA-ELIGIBLE
PATIENTS EXPOSED TO PATIENT
NAVIGATORS OR THESE COMMUNITY
HEALTH WORKERS, WOULD HAVE
IMPROVED AT HEE ADHERENCE AND ID
LABORATORY CHARACTERISTICS
REFLECTING ADHERENCE TO
HYDROXYUREA.
WE DID OUR STUDY IN SPECIALTY
CLINICS.
WE USED PRESCRIBING ALGORITHMS
IN BOTH THE CONTROL AND THE
EXPERIMENTAL ARMS.
WE RECOGNIZED THAT MERE VERBAL
ASCENT OF BEING ON HYDROXYUREA
IS NOT THE SAME AS ACTUALLY
TAKING HYDROXYUREA, SO WE TRIED
TO USE MORE SOPHISTICATED
METHODS WITH SOME SUCCESS TO
GAUGE WHETHER PATIENTS WERE
ACTUALLY TAKING THEIR
HYDROXYUREA.
MAYBE THE BIGGEST DOWN FALL OF
THIS STUDY WAS THAT THE
PHYSICIANS INVOLVED WERE BLINDED
TO WHETHER THEIR PATIENTS WERE
GETTING INTERVENTIONS BY
COMMUNITY HEALTH WORKERS.
SO IT WAS NOT A TEAM
INTERVENTION, AND THE WORK WITH
THE COMMUNITY HEALTH WORKER WAS
ISOLATED FROM THE WORK OF THE
FEZ AND WE PHYSICIAN AND WE WERE
TO TALK TO ONE ANOTHER ABOUT
WHETHER OUR PATIENTS WERE USING
HYDROXYUREA.
HAVING TROUBLE HERE.
THIS IS JUST OUR PROTOCOL FOR
HOW WE OFFERED HYDROXYUREA TO
THE PATIENT.
AGAIN, IT WAS BLINDED AND WE
USED A PRETTY MUCH STANDARD NIH
HYDROXYUREA ELIGIBILITY
CRITERIA.
WE HAD A SCRIPT AND WE
DOCUMENTED EVERY TIME WE OFFERED
THE MEDICATION TO PATIENTS, EVEN
IF THEY REFUSED AND WE CAME
BACK.
WE RECORDED ALL OF THIS AND OUR
ANALYSIS INCLUDED THE PERCENT OF
THE PEOPLE WHO WERE ELIGIBLE FOR
HYDROXYUREA WHO WERE ACTUALLY ON
IT.
AND WHETHER THAT CHANGED OVER
TIME.
WE ALSO LOOKED AT THE PERCENTAGE
OF ENROLLED PATIENTS ON
HYDROXYUREA, AND THEN THE
REASONS WHY PATIENTS WERE NOT ON
HYDROXYUREA, AND WE LOOKED AT,
OF COURSE, SELF-REPORT FOR USING
HYDROXYUREA.
THESE ARE OUR RESULTS.
A WHOLE LOT OF PEOPLE SAID THEY
WERE ON HYDROXYUREA.
AND THAT WAS KIND OF A SURPRISE
AND CERTAINLY HIGHER THAN WHAT
WE HAD ANTICIPATED AT THE
BEGINNING OF OUR STUDY.
WE DID NOT SEE ANY VARIATION IN
WHO WAS ON HYDROXYUREA BY
GENDER, OR BY PEDIATRIC VERSUS
ADULT CLINIC MEMBERSHIP.
WE DID NOT SEE ANY DIFFERENCE BY
GENOTYPE.
IT WAS A SLIGHT VARIATION BY S
BETA SURE ZERO VERSUS SS, OTHEN
THAT, NOT A LOT OF DIFFERENCE.
THE LABS.
THEY DIDN'T CHANGE THAT MUCH.
THE FETAL HEMOGLOBIN WENT UP BY
ABOUT 1 1/2 TO 2%.
THE WHITE COUNT WENT DOWN,
ABSOLUTE NEUTROPHIL COUNT WENT
DOWN, HEMOGLOBIN DIDN'T REALLY
CHANGE, THE RETIC COUNT DIDN'T
CHANGE THAT MUCH.
THIS IS FROM CONTROLS VERSUS
EXPERIMENTAL PATIENTS.
SIMILARLY, THOSE WHO GOT
NAVIGATORS IN THE EXPERIMENTAL
GROUP DID NOT HAVE NEW UPTAKE OF
HYDROXYUREA AND YOU CAN SEE THAT
THERE WAS NOT VERY MUCH ROOM FOR
IMPROVEMENT THERE.
THE DISCONTINUATION RATE WAS NOT
THAT GREAT.
OF A DIFFERENCE
BETWEEN GROUPS AS WELL.
THE ONE THING WE DID SEE IS THAT
PEOPLE WERE MORE CONSISTENT IN
THE EXPERIMENTAL GROUP AT 12
MONTHS IN TAKING THEIR
HYDROXYUREA.
SO THIS NUMBER IS A NUMBER OF
HOW MANY TIMES YOU MISSED
HYDROXYUREA IN THE LAST 30 DAYS
BY REPORT, SELF-REPORT.
AND THAT WAS A LOWER NUMBER IN
THE EXPERIMENTAL GROUP THAN IN
THE CONTROL GROUP.
AND THAT'S WHAT WE KNOW ABOUT
ADHERENCE TO HYDROXYUREA.
HERE'S ANOTHER QUESTION.
DO YOU PRESCRIBE OR OFFER
HYDROXYUREA IN EVERY PATIENT?
OR DO YOU TRY NEWER DISEASE
MODIFIERS FIRST?
AND IF YOU DO SO, WHICH ONES DO
YOU TRY?
AND DO YOU HAVE PATIENTS WHO END
UP ON COMBINATIONS OF NEWER
DISEASE MODIFIERS WITHOUT
HYDROXYUREA?
THIS IS A QUESTION A LOT OF
PEOPLE WANT TO KNOW, BECAUSE
THERE'S SO MUCH MONEY TIED UP IN
THESE MEDICATIONS AND EVERYBODY
WANTS TO GET EFFECTS THAT ARE
FAST AND DO IT CHEAPLY.
AND WHAT WE KNOW IS ISIR HAS
BEEN THE PUSHER OF THIS.
THIS IS AN OLD STUDY, THEY
RECENTLY RELEASED THEIR
INDIVIDUAL COST-EFFECTIVENESS
RATIOS FOR GENE THERAPY, THE TWO
GENE THERAPIES UP FOR APPROVAL
THIS DECEMBER.
BUT IN EITHER CASE, THIS
PUBLICATION HERE OR IN THE CASE
OF THE GENE THERAPY, THEY'RE
FINDING FOR A PAYOR PERSPECTIVE,
AND I WANT TO EMPHASIZE, THIS IS
NOT A SOCIETAL OR PATIENT
PERSPECTIVE BUT A PAYOR PORE
SPERTIVE, YOU'RE TALKING ABOUT
$88,000 A YEAR FOR THE
CRIZANLIZUMAB, 84,000 FOR
VOXELOTOR AND 24,000 FOR L GLUTE
MEAN, LEADING TO GREATER THAN A
MILLION DOLLARS PER QUALITY
ADJUSTED LIFE YEAR
COST-EFFECTIVENESS RATIOS, AND
FEW QUALITY ADJUSTED LIFE YEARS
GAINED FOR ANY OF THESE DRUGS.
WE CERTAINLY HAVE BEEN
PRESCRIBING THESE DRUGS DESPITE
THE ICER PUBLICATION.
AND PATIENTS HAVE CERTAINLY BEEN
DERIVING BENEFIT FROM THEM,
SUBJECTIVELY AND OBJECTIVELY.
SO WHAT DO WE DO?
WELL, WE TRY TO USE SHARED
DECISION-MAKING WITH THE
PATIENT.
AND WE HAVE A PAMPHLET THAT GOES
ACROSS THE SPECTRUM.
I'M NOT SHOWING YOU THE PAMPHLET
TODAY BUT BELIEVE ME, WE HAVE A
PAMPHLET JUST LIKE THIS,
NON-BRANDED, THAT WE HAND OUT TO
OUR PATIENTS IN ORDER TO EXPLAIN
TO THEM WHAT IT IS WE'RE
OFFERING AND WHAT THEY CAN DO IN
TERMS OF MAKING THEIR CHOICES,
AND IT HAS SIDE EFFECTS IN HOW
YOU TAKE IT, I HAVE TO TAKE IT
ALL MY LIFE, WHAT ARE THE
MONITORING PARAMETERS, ET
CETERA.
AND WE TRY TO LET THE PATIENTS
THINK THIS OVER AND MAKE THE
DECISION FOR THEMSELVES.
IF THEY ASK US WHERE YOU DO, WE
GIVE OUR OPINION, BUT WE TRY TO
HELP THE PATIENTS COME TO A
CONCLUSION BECAUSE IF THEY DON'T
HAVE THE BUY-IN, THEY'RE
CERTAINLY NOT GOING TO TAKE THE
DRUGS.
WHEN DO YOU HAVE THAT
CONVERSATION ABOUT CURATIVE
INTENT?
AND I WOULD SAY AT VARIOUS
POINTS.
ONE CERTAINLY INFLECTION POINT
IS AFTER A BIG EVENT.
PATIENTS WILL OFTEN SAY, I'M
SCARED, I THINK I'M GOING TO
DIE, WHAT CAN I DO?
AND THAT'S OFTEN A WINDOW TO
HAVE A CONVERSATION ABOUT
THERAPY WITH CURATIVE INTENT.
SOMETIMES NEW PATIENTS LIKE TO
HEAR THIS CONVERSATION, BUT I
WOULD SAY MOST NEW PATIENTS,
WHEN YOU'RE TRYING TO TALK TO
THEM ABOUT FOUR DIFFERENT
DISEASE MODIFIERS AND THREE
POSSIBLE DIFFERENT DISEASE --
CURATIVE DISEASE INTENT
THERAPIES, IT'S A LONG
CONVERSATION.
IT TAKES TIME AND YOU HAVE TO DO
IT OVER SEVERAL CLINIC VISIT AND
THE FAMILY HAS TO BE INVOLVED
AND IT IS NOT A VERY QUICK
DECISION.
PATIENTS CHANGE THEIR MIND
SOMETIMES, SO WE ALLOW THAT AS
WELL.
WE TRY TO GET ALL OF THE
INFORMATION THAT PATIENTS ARE
ASKING FOR, REPEATEDLY
SOMETIMES.
SO THAT'S HOW WE DO IT AND IN
THE ADULT WORLD, IT'S A LITTLE
BIT DIFFERENT BECAUSE YOU DON'T
HAVE A PARENT MAKING THE
DECISION, YOU HAVE THE ADULT AND
THEIR SIGNIFICANT OTHER.
AND THEN LAST, WHAT ARE YOU
DOING WITH OPIOID USE FOR
CHRONIC PAIN?
YOU ARE MAINLY GOING UP?
ARE YOU MAINLY KEEPING PEOPLE
THE SAME?
OR ARE YOU MAINLY DECREASING?
AND BY NOW YOU'VE ALREADY HEARD
A GREAT DEAL ABOUT OPIOIDS, THE
PROBLEMS WITH OPIOIDS.
I WOULD SAY WE'RE MAINLY GOING
DOWN, BUT WHAT ARE WE
SUBSTITUTING FOR OPIOIDS?
AND THAT'S WHERE THE PROBLEM
LIES.
GETTING PAYMENT FOR INTEGRATIVE
CARE AND FOR ANY NON-OPIOID
THERAPIES THAT DON'T INVOLVE
PHARMACEUTICALS IS DIFFICULT.
AND THAT'S WHERE THE PROBLEM IS,
AND THIS IS A KNOWN PROBLEM.
PEOPLE ARE NOT ABLE TO GET THESE
THINGS PAID FOR.
SO IT'S A DIFFICULT AND ARDUOUS
TASK TO TRY TO TAPER SOMEBODY'S
OPIOIDS.
BUT WE ARE TRYING TO DO IT WHEN
IT'S APPROPRIATE.
THAT'S ABOUT WHAT I HAVE TO SAY
ON THE THERAPEUTIC JOURNEY IN
REAL LIFE FOR MANAGING PATIENTS
WITH SICKLE CELL DISEASE, AND
I'LL BE GLAD TO TAKE QUESTIONS
AT THE APPROPRIATE TIME.
THANK YOU VERY MUCH.
[APPLAUSE]
>> SO THAT WAS A PRE-RECORDED
SESSION AND THANK YOU TO
DR. WALLY SMITH FOR THAT VERY
RICH PERSPECTIVE.
HE'S NOT ABLE TO JOIN US, BUT IF
ANYONE HAS QUESTIONS, YOU CAN
SHARE WITH THE ORGANIZERS AND
THEY WILL MAKE SURE TO GET THE
QUESTIONS TO HIM.
AND FINALLY, OUR LAST SPEAKER
FOR THIS SESSION, LAST BUT NOT
LEAST, WE HAVE DR. KARINA
YAZDANBAKHSH.
SHE'S THE VASOPRESSIN AND
DVICE PRESIDENT AT THENEW YORK N
NEW YORK.
A LONG TIME FRIEND AND
COLLABORATOR, HER CURRENT
RESEARCH IS FOCUSED ON
UNDERSTANDING MECHANISMS OF
TRANSFUSION ASSOCIATED ALLO
IMMUNIZATION, SHE'S A RECIPIENT
OF MANY NIH GRANTS AND AWARDS,
AND SHE MADE ME PROMISE I
WOULDN'T GO THROUGH ALL OF THEM.
SO KARINA.
>> THANK YOU.
>> OKAY.
SO FIRST OF ALL, THANK YOU FOR
GIVING ME THE OPPORTUNITY TO
PRESENT SOME OF OUR WORK.
SO I HAVE NOTHING TO DECLARE.
SO WE KNOW WE HAVE ANEMIA IN
SICKLE CELL DISEASE, RED CELL
DESTRUCTION CAN OCCUR EXTRA
VASCULARLY OR INTRAVASCULARLY IN
SICKLE CELL DISEASE.
WE KNOW THERE'S INTRAVASCULAR
HEMOLYSIS, AND HO1 LEVELS WHICH
BREAKS DOWN HEME IS UPREGULATED.
WE KNOW THAT EXCESSIVE HEME CAN
ACTIVATE THE UNDERLYING
ENDOTHELIUM.
YOU GET INCREASED ACTIVATION OF
ENDOTHELIAL ADHESION MOLECULES,
APOP TOLL TICK MARKERS, AND
THESE LEAD TO ATTACHMENT OF
ACTIVATED LEUKOCYTES, RED
CELLS -- WITH LEADS TO
VASOOCCLUSION.
WE ALSO KNOW FROM ANIMAL MODELS
THAT YOU INJECT FREE HEME AND
THAT INDUCES VASCULAR STASIS AND
ACUTE CHEST SYNDROME.
JUST BRIEFLY ABOUT CIRCULATING
MONOCYTES, THAT'S ARE WHAT WE
REALLY KNOW AS PRECURSORS FOR
MACROPHAGES AND DENDRITIC CELLS.
BUT THERE'S INCREASING EVIDENCE
THAT THESE CIRCULATING
MONOCYTES, WHILE IN THE BLOOD,
THEY DISPLAY INDIVIDUAL
FUNCTIONAL ACTIVITIES.
SO WE KNOW THAT THEY'RE PRODUCED
BOTH IN MICE AND IN HUMAN IN THE
BONE MARROW.
THEY GET RELEASED INTO THE
CIRCULATION, AND THERE WE CAN
DISTINGUISH THEM BASED ON
VARIOUS SURFACE MARKERS.
THIS IS FOR MOUSE, THIS IS FOR
HUMAN.
IT'S NOW BELIEVED THAT THE
MAJORITY OF THE CIRCULATING
MONOCYTES IN HUMANS, AT LEAST,
WHICH ARE CLASSICAL MONOCYTES,
THEY DIFFERENTIATE FURTHER IN
THE CIRCULATION, GIVING RISE TO
THESE NON-CLASSICAL MONOCYTES,
WE CALL THEM NOW PATROLLING
MONOCYTES.
IN MOUSE WE HAVE -- THEY HAVE
IDENTIFIED THE TRANSCRIPTION
FACTOR THAT IS IMPORTANT FOR
THIS DIFFERENTIATION.
IN HUMANS, WE STILL DON'T KNOW,
THIS IS UNDER ACTIVE RESEARCH.
WHAT ARE THESE PATROLLING
MONOCYTES THAT OUR LAB BECAME
VERY OBSESSED WITH?
SO THESE AS I SAID, THESE ARE
THESE NON-CLASSICAL MONOCYTES,
AND IT WAS SHOWN A FEW YEARS
AGO, THEY CRAWLED ALONG THE
VASCULATURE AND PHAGOCYTE -- IN
MOUSE MODELS, THEY WERE SHOWN IN
AT LEAST ATHEROSCLEROSIS MODEL,
THEY CONTROL ENDOTHELIAL DAMAGE
AND ALZHEIMER'S DISEASE MODELS,
THEY CLEAR VASCULAR AMYLOID BAY
DA.
THEY CRAWL ALONG AS I SAID AND
THEY REMOVE PARTICLES AND
DEBRIS.
WHAT WE HAD SHOWN A FEW YEARS
AGO THAT THESE NON-CLASSICAL
ONES OR THESE PATROLLING
MONOCYTES EXPRESS HIGH LEVELS OF
H01, AND WHAT WE WERE MORE
INTERESTED IN WAS THEIR ABILITY
OF THESE PATROLLING MONOCYTES
EXPRESSING THESE HIGH LEVELS AND
CONTROLLING UNDER HEMOLYTIC
CONDITIONS T-CELL
ANTI-INFLAMMATORY PROFILE.
WE'VE NOW GONE ON TO SHOW THAT
THESE PETROLEUM MONOCYTES REMOVE
ENDOTHELIAL ATTACHED SICKLE RED
CELLS.
THIS WAS -- FOR US WAS A BIG
FINDING BECAUSE NOW WE CAN THINK
OF THAT THEY MAYBE ARE ALSO
INVOLVED IN CONTROLLING
VASOOCCLUSION, AND ACTUALLY WHAT
WE FOUND WAS THAT AT STEADY
STATE COMPARED TO HEALTHY
DONORS, PATIENTS HAD REDUCED
NUMBERS OF THESE PATROLLING
MONOCYTES, SPECIFICALLY
FREQUENCIES, AND THEIR NUMBERS
WAS EVEN FURTHER REDUCED WHEN
THE PATIENT WAS EXPERIENCING
ACUTE CRISIS.
SO WE SHOWED THAT PATROLLING
MONOCYTES ARE CORRELATED
NEGATIVELY WITH VASO-OCCLUSIVE
CRISIS IN SICKLE CELL, AND KIND
OF INDICATING MAYBE THEY ARE
REALLY INVOLVED IN PROTECTING
THE VASCULAR END TEAL YUM BY
THEIR ABILITY TO REMOVE THE
SICKLED ATTACHED CELLS.
IN FACT IF WE MANIPULATED THEIR
NUMBERS IN MOUSE MODELS, ALL THE
MOUSE MODELS NOW, WHAT WE FOUND
WAS WE COULD POTENTIALLY
DECREASE THE AMOUNT OF STASIS IF
WE INCREASE THEIR NUMBERS IN
THESE SICKLE MOUSE MODELS, THE
TOWNES MODEL, AND IF WE REMOVE
THEM, YOU REALLY EXASPERATED THE
INFARCTS THAT WE SAW IN THE
PATHOLOGY, AS WELL AS THE
ATTACHMENT, THE STASIS TO THE
VASCULAR WALL.
SO WHAT WE ASKED WAS MORE LIKE
WHY IS IT THAT THESE PATROLLING
MONOCYTE NUMBERS ARE LOW?
JUST THAT STEADY STATE, NOT
DURING VASO-OCCLUSIVE CRISIS,
JUST STEADY STATE.
AS I SAID, THERE'S INCREASING
EVIDENCE THAT PATROLLING
MONOCYTE ARE DERIVED FROM
CIRCULATING MONOCYTES SO OUR
FOCUS TURNED TO THESE CLASSIC
MON TYPES, AGAIN BASED ON
SURFACE MARKERS, THAT'S HOW WE
DISTINGUISH THEM.
BY SELF-SORTING THESE FROM
PATIENTS AND COMPARING THEM TO
CONTROLS, WE FOUND SICKLE
PATIENTS -- THE LEVELS OF GENES
THAT DEPICT THE INTERFERON ONE,
INTERFERON SIX SIGNATURE
RESPONSE GENE WAS ELEVATED.
AND WE ALSO WENT INTO THE
PLASMA, AND THIS WAS ACTUALLY
ALSO SHOWN FOR NEW TRIP FILLS AT
THE SAME TIME AND ALSO TOTAL MOM
KNOW SITE BYMONOCYTE BY LOOKINGR
GROUPS.
IN SICKLE MICE WE SAW THIS
INTERFERON CYTOKINE.
WE STARTED LOOKING AT A LOT OF
ASSOCIATION WITH VARIOUS
CHARACTERISTICS OF THESE
PATIENTS, AND WHAT WE FOUND WAS
A NICE CORRELATION BETWEEN TOTAL
HEME IN THE PLASMA OF PATIENTS
AND THEN THESE INTERFERON, TYPE
I INTERFERON ALPHA LEVELS.
SO THIS SUGGESTED THAT TO US
THAT MAYBE IT'S HEMOLYSIS, THE
HEME THAT IS INDUCING THE
INCREASE INTERFERON -- TYPE
1 INTERFERON.
SO WE WENT BACK TO OUR MODEL,
WILD TYPE MICE, AND WE INDUCED I
A CUTE HEMOLYSIS.
AND THEN LOOKED FOR THIS
INTERFERON IN THE BLOOD THE NEXT
DAY, AND WHAT WE FOUND THAT IN
FACT INTERFERON ALPHA LEVELS
INCREASED WITH ALL THESE
TREATMENTS.
I DON'T HAVE TIME TO GO INTO IT
BUT THIS IS ALL PUBLISHED.
WHAT WE FOUND WAS IT WAS THE --
THEY WERE RELEASING THIS
INTERFERON INTO THE CIRCULATION,
AND WE LOOKED AT THE PATHWAY,
THE SIGNALING PATHWAY THAT WAS
IMPORTANT, IT WAS
TLR4 INDEPENDENT, BUT IT WAS
THROUGH THE SIGNALING PATHWAY,
TBK1, AND THEN THE I CAP PA B
KINASE EPSILON.
AND THIS WAS KIND OF INDUCING
THE INTERFERON TO BE PRODUCED
AND THEN THIS TYPE 1 INTERFERON
GOES AND INDUCES A DOWNSTREAM
SIGNAL, MULTIPLE GENES ARE
ACTIVATED AND THE ONE THAT
CAUGHT OUR ATTENTION WAS THIS
CHEMOKINE LIGAND 2CCL2.
WHAT THIS CHEMOKINE DOES IS IT
RECRUITS MONOCYTES TO INJURED
TISSUE.
WHAT WE FOUND WAS JUST LIKE IT
HAD ALREADY BEEN DESCRIBED IN
HUMANS THAT THEIR LEVELS WERE
INCREASED IN SICKLE PATIENTS AND
WHAT WE FOUND IN SICKLE MICE WAS
INCREASED AND THEN JUST TO
CONFIRM THAT THIS WAS THE CC
WILL 2 WAS DOWNSTREAM OF THIS
HEME INDUCED INTERFERON, WE USED
THIS INTERFERON RECEPTOR
KNOCKOUT MICE, INJECTED THEM
WITH HEME.
AS YOU SEE, THIS IS THE CONTROL,
YOU SEE UPREGULATION OF CCL2 BUT
IN THIS INTERFERON RECEPTOR
KNOCKOUT MICE NOW THE EFFECT OF
HEME YOU DON'T SEE THE CCL2 AS
MUCH BEING PRODUCED INDICATING
THAT IS DEFINITELY CCL2 IS
DOWNSTREAM OF THIS HEME INDUCED
INTERFERON RESPONSE.
SO THIS IS WHAT IT'S DOING, THE
CHEMOKINE, IT TELLS THE
CLASSICAL MONOCYTE COME INTO THE
TISSUE, INJURED TISSUE, AND
THERE IT JUST DIFFERENTIATES
DOWN THIS PATHWAY, AND WE CAN
DISTINGUISH THESE DIFFERENT CELL
TYPES, DIFFERENTIATION STEPS BY
USING VARIOUS MARKERS DEPICTED
HERE AND BASICALLY WHAT WE FOUND
IN THESE SICKLE MICE, WE SEE
MICE INCREASE IN CLASSICAL
MONOCYTES IN THE LIVER, MORE SO
THAN IN THE SPLEEN, AND
IMPORTANTLY THE NEXT STEP OF
DIFFERENTIATION, IN THE LIVER
YOU SEE A LOT OF THESE TRANSIENT
MONOCYTES WHICH ARE GOING DOWN
THAT PATHWAY, SIX FOLD INCREASE.
AND THE BEST ONE WAS THIS
MONOCYTE DERIVED MACROPHAGES
FURTHER DOWN AND WAS, AGAIN, IN
THE LIVER.
REALLY, THIS WAS 13 FOLD
EXPANSION OF THESE MONOCYTE
DERIVED MACROPHAGES.
AND THIS IS JUST SHOWING THAT IF
YOU INJECTED THE MICE WITH HEME,
YOU ALSO SAW EXPANSION OF THESE
MONOCYTE DERIVED MACROPHAGES AND
SIX FOLD HERE, AND THIS THIS WAS
CURTAILED IF YOU USED THE
INTERFERON RECEPTOR KNOCKOUT
MICE AGAIN FOLLOWING INJECTION
OF HEME, OR YOU USE THE RECEPTOR
THAT BINDS TO CCL2, THE KNOCKOUT
OF THAT, AND ALSO THAT ALSO DID
NOT RESPOND TO THE EFFECTS OF
HEME.
SO WHAT WE HAVE IS THAT -- SO
YOU HAVE YOUR RESIDENT
MACROPHAGE PRODUCING THE
INTERFERON, THAT INDUCES CCL2,
THIS CHEMOKINE THAT TELLS THE
BLOOD CLASSICAL MONOCYTE, COME
IN TO THE LIVER WHERE IT JUST
NOW DIFFERENTIATES AND
EVENTUALLY IS GOING TO GO INTO
THE MACROPHAGE POOL.
SO AS I SAID, THE CLASSICAL
MONOCYTE IS SUPPOSED TO GIVE
RISE TO THIS PATROLLING MONOCYTE
IN THE BLOOD, BUT IF IT'S GOING
ALL THE TIME INTO THE LIVER,
COULD IT BE THAT WE JUST ARE
KIND OF THE BALANCE IS NOW
PERTURBED IN SICKLE CELL AND
THAT IS WHY YOU HAVE THIS
DIFFERENTIATION NOT HAPPENING AS
EFFECTIVELY UNDER TH THESE
HEMOLYTIC CONDITIONS THAT I
DESCRIBED.
SO TO UNDERSTAND, TO KIND OF
EXPLORE THIS IDEA FURTHER, WE
LOOKED AT ADDITIONAL MONOCYTE
FACTORS, SO WE KNOW WITH HAVE
MONO CYTOSIS IN SICKLE CELL, AN,
BEING PRODUCED FROM THE BONE
PLAYER OWFROM THE BONEMARROW IN.
WE LOOKED AT ONE KEY FACTOR FOR
MONOCYTES WHICH IS CSF-1.
AND WE SAW THOSE LEVELS WERE
INRECREASINCREASED IN OUR SICKLS
AS WELL AS OUR MICE SO AGAIN WE
INJECTED HEME TO SEE IF THAT
LEVEL GOES UP AND OF COURSE,
AGAIN, WE SAW -- NOT OF COURSE.
WE SAW INDUCTION OF
CSF-1 DOSE-RESPONSE HERE JUST
SHOWING THE DOSE-RESPONSE TO THE
EFFECTS OF HEME AND THEN IF WE
PRE-TREATED MICE WITH HEMOPEXIN
YOU DIDN'T SEE THE UPREGULATION
OF CSF-1, REALLY INDICATING THAT
HEME IS THE ONE THAT IS INDUCING
THE CSF-1 IN OUR WILD TYPE MICE
HERE.
SO WHAT ABOUT NOW STARTING TO
MANIPULATE THE CSF-1 LEVELS TO
SEE IF WE'RE AFFECTING MONOCYTE
PATROLLING NUMBERS.
SO THAT'S WHAT WE DID, WE
INJECTED CSF-1 AND BOTH NUMBERS
INCREASED IN THE CIRCULATION,
BUT ACTUALLY IT WAS THE
PATROLLING MONOCYTE ONE IN RED
THAT JUST KEPT GOING ON.
REALLY SPECIFICALLY EXPANDING
THE PATROLLING MONOCYTE AS
OPPOSED TO THE CLASSICAL ONES,
AND AT THE SAME TIME THAT WE
WERE DOING THIS, PAPER CAME OUT
IN IMMUNITY SHOWING THAT
CSF-1 ACTUALLY DOES INDUCE
PATROLLING MONOCYTE NUMBERS TOO.
SO WHAT ABOUT IF WE PREVENTED --
BLOCKED CSF-1 LEVELS WITH
ANTIBODIES, AND THAT'S WHAT WE
FOUND, IT REALLY EFFECTIVELY
TARGETED PATROLLING MONOCYTE
NUMBERS HERE, BUT NOT THE
CLASSICAL MONOCYTE.
SO HAVING ESTABLISHED CSF-1 IS
PLAYING A ROLE IN CONTROLLING
PATROLLING NUMBERS, NOW THE NEXT
QUESTION WAS, WE WERE JUST KIND
OF CURIOUS WHAT IS GOING ON.
SO HEMOLYSIS ON ONE HAND, RIGHT,
IS -- SO AGAIN, I DON'T HAVE
TIME TO SHOW THAT -- WE SHOWED
THAT HEMOLYSIS THROUGH
ENDOTHELIAL AND RF2 IS
RESPONSIBLE FOR INDUCTION OF CSF
ONE AND THIS IS IMPORTANT FOR
PATROLLING MONOCYTE
DIFFERENTIATION FROM THE
CLASSICAL MONOCYTE, BUT AT THE
SAME TIME, HEMOLYSIS AS I SAID
FROM TYPE I INTERFERON INDUCES
CCL2 TO BECOME MACROPHAGES.
SO BASICALLY IT'S REALLY -- IT'S
GOING TO BE A BATTLE BETWEEN CSF
1 AND CCL2 THAT'S GOING TO
CONTROL THESE PATROLLING
MONOCYTE NUMBERS, AT LEAST
THAT'S WHAT WE HYPOTHESIZED.
AND THAT'S ACTUALLY WHAT WE
FOUND, IF YOU JUST LOOK AT CSF-N
OF THE PATIENTS AND PATROLLING
MONOCYTE NUMBERS, THERE WAS
HARDLY NR CORRELATION.
CCL2, WE SAW IT WAS LIKE A TREND
TOWARDS THE LEVELS CORRELATED
WITH PATROLLING MONOCYTE
NUMBERS, BUT IT WAS REALLY THE
RATIO BETWEEN THE CSF-1 TO
CCL2 THAT WAS DETERMINING
PATROLLING MONOCYTE NUMBERS.
SO WHAT IS HAPPENING THE WAY
WE'RE THINKING ABOUT THIS, IN
THE VASCULATURE, YOU HAVE THE
CLASSICAL MONOCYTES, YOU HAVE
THE CSF-1 INDUCING PATROLLING
MONOCYTES TO BE PRODUCED, BUT AT
THE SAME TIME, CCL-2 IS TELLING
THE CLASSICAL MONOCYTE TO GO
INTO THE TISSUE.
AND DIFFERENTIATE THERE.
SO WE ASK, WHAT IF WE BLOCKED
THIS TRANS MIGRATION OF THIS
CLASSICAL MONOCYTES GOING INTO
THE TISSUE?
WOULD WE GET AN INCREASE IN
PATROLLING MONOCYTE NUMBERS?
AND WE SHOWED IN VITRO, AT
LEAST, AGAIN I DON'T HAVE TIME
BUT IT'S IN THE PAPER, THAT IT
PREVENTS THIS TRANS MIGRATION
AND IT'S KNOWN TO DO THAT.
SORE WHAT WE DID -- SO THIS IS
WHAT WE DID.
WE USE OUR SICKLE MICE, THIS IS
MY LAST DATA SLIDE, WE
PRE-TREATED MICE WITH EITHER
ANTIP SELECTIN OR ISOTYPE
CONTROL AND/OR PLUS CSF-1.
SO THE IDEA BEING THAT ANTIP
SELECTIN WILL PREVENT THE TRANS
MIGRATION, WE SHOULD GET MORE
PATROLLING MONOCYTES,
CSF-1 HELPING THE
DIFFERENTIATION OF PATROLLING
MONOCYTES, LET'S SEE.
SO CLASSICAL MONOCYTE IN THE
BLOOD, NOTHING HAPPENED, THERE
WAS NO DIFFERENCE.
HOWEVER, ONCE WE GAVE THE MICE
ANTIP SELECTIN, WE SAW INCREASE
IN PATROLLING MONOCYTE NUMBERS.
IF WE GAVE THEM ANTIP SELE
SELECTINCO -- CSF-1, THE NUMBERS
WENT UP MORE.
WHAT WAS MORE IMPORTANT, AGAIN,
WITH ANTIP SELECTIN ALONE,
STASIS WENT DOWN.
BUT COAB ADMINISTRATION -- WAS
MORE EFFECTIVE IN PREVENTING
STASIS.
CSF-1 WAS BETTER AT CONTROLLING
CELL DEATH WHEN GIVEN ACTUALLY
BY ITS OWN.
AGAIN, AS EXPECTED, ANTIP
SELECTINPREVENTED THIS CLASSICAL
MONOCYTES GOING INTO THE LIVER.
CSF-1 HAS NO EFFECT IN THIS
ASPECT.
IT JUST AFFECTS PATROLLING
MONOCYTE IN THE -- IN BLOOD.
ALSO WITH LIVER FURTHER DOWN
DIFFERENTIATION, WE DIDN'T SEE
AN EFFECT BUT HOWEVER CSF
CSF-1 AGAIN ANTIP
SELECTININHIBITED THE NUMBERS OF
THESE TRANSIENT MONOCYTES IN THE
LIVER.
SO IT'S PREVENTING THE CLASSICAL
MONOCYTES GOING INTO THE LIVER.
SO THIS IS OUR WORKING MODEL.
WE'RE SAYING THE CLASSICAL
MONOCYTES ON ONE SIDE CAN BECOME
MACROPHAGES ON THE OTHER, BECOME
PATROLLING MONOCYTES,
DIFFERENTIATE IN THE BLOOD OR GO
TO THE TISSUE.
WE'RE SAYING THAT TYPE I
INTERFERON THROUGH CCL2 UNDER
HEMOLYTIC CONDITIONS DRIVES THE
MACROPHAGE DIFFERENTIATION IN
HOWEVER IN THE CIRCULATION IS
THE RF2CS -- SO IT'S REALLY THE
RATIO OF THESE TWO THAT IS GOING
TO DECIDE HOW MUCH PATROLLING
MONOCYTE ARE GOING TO STAY IN
THE VASCULATURE.
IF THIS LEVEL IS HIGH RELATIVE
TO THIS LEVEL, TO CCL2, YOU SEE
AN EXPANSION OF THESE PATROLLING
MONOCYTES.
AND MAYBE THIS COULD BE A WAY TO
INCREASE THEIR NUMBERS AND AS A
RESULT, IF YOU HAVE HIGHER
PATROLLING NUMBERS, YOU'RE GOING
TO PREVENT VASO-OCCLUSIVE CRISIS
EVENT.
ANTIP SELECTINHIGH PRESSURE
ININ DIFFERENTIATESTHIS POSITIOT
BLOOD PATROLLING MONOCYTES
SHOULD GO UP WITH ANTIP SELECTIN
BUT THIS IS ONLY GOING TO HAVE
IF YOU HAVE THESE TWO RATIOS
THERE.
SO IT'S POSSIBLE THAT THE
STUDIES WITH CRIZ THAT HAVE NOT
WORK, IT COULD BE, WE'RE
POSTULATING, THAT REALLY WE HAVE
TO BE LOOKING AT THE RELATIVE
RATIOS OF THESE CCL-2 TO
CSF-1 AS WELL AS PATROLLING
MONOCYTE NUMBERS IN THOSE
PATIENTS.
HOWEVER, WE THINK IT IS THE
COMBO, THE ANTI-P SELECTIN PLUS
CSF-1 THAT REALLY IS GOING TO
IMPROVE BLOOD PATROLLING
MONOCYTE NUMBERS, AND THAT'S
GOING TO BE REALLY EFFECTIVE IN
PREVENTING -- WITH THAT I'D LIKE
TO THANK THE PEOPLE, JUST
BRILLIANT, WE'VE BEEN WORKING
TOGETHER FOR A WHILE, THIS IS MY
LAB, GRATEFUL TO THE NYBC SICKLE
CELL TRANSFUSION RESEARCH GROUP.
WE HAVE, OF COURSE, OUR CLINICAL
COLLABORATORS, AND OF COURSE
NONE OF THIS WORK WOULD HAPPEN
WITHOUT FUNDING SUPPORT FROM
NHLBI.
THANK YOU.
[APPLAUSE]
>> THANK YOU, KARINA.
THERE IS ONE QUESTION IN THE
CHAT.
IT'S FROM SHAINA ALLEN.
FANTASTIC TALK.
ARE YOU ABLE TO SEE A DIFFERENCE
IN MONOCYTE DIFFERENTIATION WITH
AGE AND YOU HAVE LOOKED AT THE
ROLE OF NOTCH SIGNALING IN THIS
PROCESS, GIVEN THAT IT HAS BEEN
SHOWN TO BE DISREGULATED IN
AGING?
CURIOUS IF PLAYING A ROLE IN
SICKLE CELL DISEASE AND RAPID
AGING PHENOTYPE.
>> THANKS.
THAT'S A GREAT QUESTION.
SO ALL I CAN TELL YOU, THE NOTCH
SIGNALING, WE'RE LOOKING AT THAT
FOR EXPANDING THESE PATROLLING
MONOCYTE IN VITRO, SO WITH
RESPECT TO AGING, IN PATIENTS,
NO WE HAVEN'T LOOKED AT IT.
IN MICE, WE'RE LOOKING AT IT.
>> THANKS, KARINA.
ALL RIGHT.
SO THAT BRINGS US TO THE END OF
OUR SESSION.
THANK YOU, EVERYBODY, FOR
STAYING AND THANK YOU VERY MUCH
TO ALL THE SPEAKERS.
APPRECIATE IT.
[APPLAUSE]
>> SO THANK YOU ALL FOR STAYING
TO THE VERY END.
AND WE LOOK FORWARD TO ANOTHER
DAY.
SO HOPEFULLY WE'LL BE MORE
KEEPING WITH THE TIME.
THANK YOU TO THE CHAIRS AND THE
SPEAKERS.
[APPLAUSE]