GOOD AFTERNOON, WE'RE ALL GLAD YOU'RE HERE. THIS IS THE THIRD WEEK IN A ROW THAT MOTHER NATURE HAS SEPARATED THE DETERMINED FROM THOSE WHO CHOOSE TO WATCH ONLINE. I'M NOT ENCOURAGING YOU TO DO IT BECAUSE BEING HERE, YOU HAVE THE OPPORTUNITY TO SEE, TO HEAR DIRECTLY, AND ALSO TO ASK QUESTIONS AND DISCUSS, WHICH IS WHAT THE PURPOSE OF THIS WHOLE THING IS. IS THERE ANYONE WHO HASN'T BEEN HERE BEFORE TO ANY DEMYSTIFYING MEDICINE SESSION? OKAY. YOU KNOW WHAT THAT IS. WHAT IS IT? OF COURSE, THE BROOKLYN BRIDGE. AND YOU KNOW WHY WE HAVE IT AS A LOGO? BECAUSE WE'RE ALL BRIDGE BUILDERS AND WE'RE TRYING TO CONNECT EXCITING THINGS AND MORE BASIC SCIENCE WITH MAJOR HEALTH PROBLEMS AND HAVE PEOPLE COMMUNICATE ACROSS THE MEDICAL SCIENCE EAST RIVER SYMBOLICALLY THE WAY THE BROOKLYN BRIDGE DOES. IF ANY OF YOU ARE IN NEW YORK CITY AND WANT TO HAVE A VERY INEXPENSIVE AND EVEN ROMANTIC EXPERIENCE, I URGE YOU TO WALK ACROSS THE BROOKLYN BRIDGE FROM MANHATTAN, WHICH IS THAT SIDE, TO BROOKLYN, WHICH IS THIS SIDE, AT ABOUT 4:00 OR 5:00 IN THE AFTERNOON, WHEN THE SUN IS SETTING, AND YOU SEE THE STATUTE OF LIBERTY, AND YOU TAKE SOME WINE, CHEESE AND YOUR SIGNIFICANT OTHER, AND IT'S A VERY CHEAP DATE BUT ONE THAT IS MEMORABLE. I REMEMBER TAKING IT MANY TIMES. OKAY. JUST A COUPLE OF WORDS OF THINGS I FOUND INTERESTING AND MAYBE WILL HELP A LITTLE BIT TO PUT SOME THINGS IN PERSPECTIVE. IT TURNS OUT THE WORDS WE ASSOCIATE WITH THE ENTITY BEING DISCUSSED TODAY, HERPES ZOSTER, ACTUALLY PRETTY MUCH DESCRIBE THE DISEASE. SO THE PEOPLE WHO FIRST DESCRIBED THIS IN I THINK THE 18TH CENTURY USED THE GREEK WORD HERPES, WHICH MEANS SOMETHING THAT'S SORT OF CREEPING, AND THE GREEK WORD FOR GIRDLE, WHICH WAS PREVALENT IN THOSE DAYS, NOW YOU MIGHT CALL IT A BELT, WHICH I THINK IT MEANS THE SAME, IS ZOSTER, AND INTERESTINGLY ENOUGH, THE LATIN WORD FOR THE SAME THING IS CINGULUS, WHICH SOMEWHERE A ALONG THE LINE GOT MOVED INTO SHINGLES. SO SHINGLES IS NOT SUPPOSED TO BE LIKE WHAT YOU SEE ON THE SIDE OF A HOUSE. THINK OF SHINGLES AS PART OF A CREEPING BELT. IF YOU DON'T KNOW NOW, YOU WILL KNOW BY THE END OF THIS SESSION WHY THIS TERM IS ACTUALLY A VERY VALID DESCRIPTION, AND IT SHOWS THE WISDOM OF POSITIONS AND OBSERVERS. I WON'T DWELL ON THIS BUT A COUPLE OF THINGS STRUCK MY INTEREST. ONE IS THAT THE IDEA THAT THIS WAS A DISEASE OF THE DORSAL ROOT GANGLIA WAS MADE BY A BRITISH PHYSICIAN WHO IS WELL-KNOWN BECAUSE HIS NAME IS ON ONE OF WHAT USED TO BE ONE OF THE MOST COMMON FORMS OF KIDNEY DISEASE. IN THOSE DAYS, YOU COULD BE A GOOD NEPHROLOGIST AND YOU COULD OBSERVE YOUR PATIENTS AND MAKE OBSERVATIONS ABOUT THINGS THAT WERE IN TODAY'S WORLD PROBABLY CONSIDERED SOMEWHAT OUT OF YOUR --, THE NEED FOR A DIFFERENT KIND OF BRIDGE. THEN THIS FASCINATING ASSOCIATION WITH CHICKEN POX, WHICH WILL BE DISCUSSED AND I WON'T DWELL ON, BUT THE TWO THINGS THAT STRUCK ME OF INTEREST THAT I DIDN'T KNOW, I DIDN'T KNOW IT WAS GOING TO BE MENTIONED TODAY, I FOUND A PAPERBACK IN EARLY 20TH CENTURY, WHERE A PHYSICIAN TOOK SOME MATERIAL FROM A SHINGLES PATIENT AND GAVE IT TO SOME VOLUNTEERS, IT WAS A DIFFERENT WORLD THEN, AND LO AND BEHOLD, THEY CAME DOWN WITH CHICKEN POX. AND THEN TOM WELLER AT HARVARD, WHO GOT THE NOBEL PRIZE SEVERAL YEARS LATER, SHARED IT FOR CULTURING POLIO VIE RU HE VIRUS, HE ACTUALLY ISOLATED THE VIRUS. SO HERE WE ARE IN THE 21ST CENTURY. SO AMONGST THE THINGS I TRUST WILL BE DISCUSSED AND I HOPE YOU WILL ALL ENGAGE IN ARE IMPORTANT QUESTIONS. IS THIS A BENIGN DISEASE? THE OLD LITERATURE KIND OF MAKES IT OUT TO BE, YOU KNOW, IT'S PAINFUL BUT IT GOES AWAY. DO PEOPLE HAVE A NEW INFECTION, OR IS THIS A RECRUDESCENCE OF AN OLD INFECTION? DO YOU DEVELOP IMMUNITY? AND HOW EFFECTIVE IS THE VACCINE, WHICH WE HEAR A GREAT DEAL ABOUT THESE DAYS, AND PERHAPS MOST IMPORTANTLY, WHAT'S NEXT? SO WE'RE VERY FORTUNATE TO HAVE TWO NIH COLLEAGUES WHO ARE EXPERT IN THIS. AND THEY'RE GOING TO DISCUSS HERPES ZOSTER I, AND WE ENCOURAGE YOU, PLEASE, TO INTERRUPT, IF THERE'S SOMETHING YOU DON'T UNDERSTAND, QUESTIONS, EVEN DURING THE COURSE OF THE TALK. THE MORE QUESTIONS THAT COME IN, THE MORE YOU WILL FEEL INVOLVED IN IT. OKAY? NOW I HAD A -- OKAY. SO ARE YOU SPEAKING FIRST, LESIA? OR ARE YOU GOING TO INTERVIEW THE PATIENT? OKAY. SO LESIA DROPULIC IS A SENIOR STAFF PHYSICIAN HERE AT NIAID. SHE HAD TRAINING IN INFECTIOUS DISEASES DURING HER MEDICAL RESIDENCY, SHE TRAINED AT JOHNS HOPKINS, AND HERE AMONGST HER MANY ACTIVITIES, SHE IS ACTUALLY THE PRINCIPAL INVESTIGATOR OF THE HERPES VACCINE TRIAL, WHICH YOU WILL HEAR A GOOD DEAL ABOUT. AND OUR SECOND SPEAKER IS JEFF COHEN. HE GRADUATED, HE'S A PHYSICIAN, GRADUATED FROM HOPKINS AFTER A RESIDENCY IN DUKE, AND HE CAME HERE AS A STAFF FELLOW, WEP WENT TO HARVARD AS A FELLOW IN INFECTIOUS DISEASES AND THEN CAME BACK TO NIH, I THINK IN 1990, AND HE'S THE CHIEF OF THE LABORATORY OF INFECTIOUS DISEASES AND NIAID. A VERY IMPORTANT PHYSICIAN, AND HE'S BEEN THERE SINCE 2010. JEFF IS WIDELY KNOWN FOR HIS WORK, MAYBE YOU SAW, WE PUT ON THE WEBSITE, A RECENT REVIEW OF THIS TOPIC, WHICH APPEARED IN THE NEW ENGLAND JOURNAL OF MEDICINE. SO WE'RE VERY GRATEFUL TO BOTH OF YOU, AND WE'RE VERY GRATEFUL TO YOU, NICE LADY, WHO'S OFFERED TO COME AND SHARE YOUR EXPERIENCE WITH THIS GROUP, WHICH I'VE DESCRIBED TO YOU. SO THANK YOU. >> THANK YOU VERY MUCH FOR THE IPT DUCKS, AND THANINTRODUCTION, AND THANK YOU FOR TAKING THE TIME TO COME TO THE NIH. SO WE WANTED TO SHARE WITH YOU ALL HER EXPERIENCE WITH SHINGLES, OR OTHERWISE KNOWN AS HERPES ZOSTER. SO IF YOU CAN TELL US WHEN IT STARTED, WHAT WERE YOU EXPERIENCING, HOW IT PROGRESSED? >> I NOTICED THE TUESDAY BEFORE CHRISTMAS THE BACK OF MY HAIRLINE, I FELT A LITTLE BUMP. WEDNESDAY, I FELT TWO MORE BUMPS BEHIND MY EAR. AND THEN BY WEDNESDAY NIGHT, I HAD FOUR. THREE BEHIND MY EAR, IN MY HAIRLINE, AND ONE AT THE BOTTOM. THURSDAY, I WAS OKAY. CHRISTMAS DAY, I WAS OKAY. THE SATURDAY MORNING AFTER CHRISTMAS, WHEN I WOKE UP, THE RIGHT SIDE OF MY FACE JUST FELT WEIRD. SO I PUT MY HAND UP THERE AND I FELT ALL THESE LITTLE LUMPS, AND I JUST SCREAMED FOR MY NIECE. SHE CAME IN, SHE TOOK A LOOK, I'VE ALSO BEEN DIAGNOSED WITH LUPUS, AND I SOMETIMES HAVE TO HAVE HELP GETTING OUT OF BED. SO SHE HELPED ME OUT OF BED, AND WE WENT TO THE MIRROR, BUT I REALLY COULDN'T SEE BACK HERE. I COULD JUST FEEL. THAT WAS CHRISTMAS DAY, BUT THEN SATURDAY MORNING, LIKE I SAID, WHEN I WOKE UP, IT WAS JUST COVERED, THE RIGHT SIDE OF MY FACE. SUNDAY -- >> CAN YOU DESCRIBE WHAT IT LOOKED LIKE A LITTLE MORE IN THE MIRROR, WHAT YOU SAW? >> IF YOU'VE EVER HAD SUNBURN AND YOUR SKIN GOT MOIST AND THE LITTLE BUBBLES APPEAR, SOME OF THEM RAN TOGETHER, SOME DEPARTMENT, THERE WERE ALL DIFFERENT SIZES AND WHATNOT. THAT'S WHAT THE SHINGLES LOOK LIKE. I DIDN'T FEEL ANY SEVERE PAIN UNTIL THAT FOLLOWING TUESDAY. BUT BY THAT TIME, I WENT TO MY DERMATOLOGIST, TOLD HIM WHAT I READ ONLINE, DIDN'T WANT TO LOOK AT THAT AGAIN, AND HE GAME BACK AND HE SAID, YES, YOU HAVE SHINGLES. FIRST I WANTED TO KNOW HOW DID I GET IT, IS IT SOMETHING THAT'S PASSED DOWN FROM GENERATION TO GENERATION, AND THE ANSWER WAS NO. I HAD A PRESCRIPTION FILLED BY THE DOCTOR. WITHIN, I'D SAY, FIVE DAYS, THE BLISTERS WAS CLEARING UP, THE PAIN LASTED FROM TUESDAY TO FRIDAY, AND THE PAIN WAS SO SEVERE, ALL I COULD DO WAS SIT ON THE SIDE OF THE BED AND JUST CRY. COLD COMPRESS DOESN'T HELP, WARM COMPRESS DOESN'T HELP, THE FACT THAT YOU PUT YOUR HAND UP HERE, IT DOESN'T HURT BUT IT DOESN'T HELP, THE PAIN WAS LIKE UNDER THE SKIN. YOU JUST HAD TO WAIT IT OUT. I FOUND OUT THAT I WAS IN A CONTAGIOUS STAGE, WHICH REALLY CONCERNED ME BECAUSE I WORK FOR A DEFENSE COMPANY SO I'M AROUND PEOPLE ALL THE TIME. CHRISTMAS DAY I WAS WITH ALL OF MY LITTLE FAMILY MEMBERS THAT I HADN'T SEEN IN A LONG TIME, SO I THOUGHT THAT I WAS GOING TO TBIF IT TGIVEIT TO THEM, AND IT WAS NOT A REALLY GOOD FEELING TO THENG THINK THAT YOU GAVE YOUR KIDS SOME KIND OF DISEASE. BUT I CALLED ALL THE PARENTS, THE KIDS EITHER HAD CHICKEN POX OR THEY'VE HAD THE CHIC CHICKEN POX VACCINE BECAUSE THAT'S REQUIRED IN MONTGOMERY COUNTY PUBLIC SCHOOLS, SO THAT WAS FINE, BUT ON MY JOB, I GAVE A LIST OF NAMES OF ALL THE PEOPLE I TALKED TO. OUR BUILDING SERVICE PERSON CALLED THE SAFETY MANAGER, TOLD HIM WHAT WAS HAPPENING BECAUSE THEY THOUGHT THEY WERE GOING TO HAVE TO SCRUB DOWN MY DESK AREA. HE ASKED, DID ANY OF MY BLISTERS POP, AND NO, THEY DID NOT. AND HE SAID THAT WAS THE ONLY WAY THAT I COULD PASS THE SHINGLES OFF TO SOMEONE ELSE, IS IF MY BLISTERS POPPED AND THE LIQUID GOT ON A PERSON. AND THEN THEY WOULD END UP HAVING SHINGLES. I FEEL FORTUNATE BECAUSE MY PAIN WAS ONLY FOUR DAYS, AND I'VE BEEN HEARING SOME PEOPLE'S PAIN LASTS FOR A MONTH, TWO MONTHS, THREE MONTHS. AND THEY HAVE THE BLISTERS, THE REDNESS. YOU JUST DON'T FEEL GOOD. AND THERE'S NOTHING YOU CAN DO ABOUT IT WITHOUT THE MEDICATION. WHILE I WAS TAKING THE MEDICATION, I JUST HAD TO DEAL WITH THE PAIN. THE ONLY THING I COULD DO WAS CRY. >> CAN YOU DESCRIBE THE CHARACTER OF THE PAIN A LITTLE BIT MORE? >> NOT REALLY SHARP, I'VE COMPARED IT WITH A REALLY BAD TOOTHACHE OR CHILDBIRTH. IT IS BAD. IT HURTS. AND LIKE I SAID, YOU CAN'T DO ANYTHING ABOUT IT. THE MEDICATION TAKES A COUPLE DAYS TO GET IN YOUR SYSTEM. OTHER THAN THAT, YOU JUST DEAL WITH IT. YOU EITHER PULL YOUR HAIR OUT OR I DON'T REMEMBER SUICIDE OR ANYTHING LIKE THAT, BUT CRY. >> DID YOU HAVE ANY ITCHING ASSOCIATED WITH IT AT ALL? >> NOT UNTIL AFTER THE BLISTERS HAD KIND OF DRIED UP AND THE ONLY ITCHING HI WAS TH I HAD WAS THE BLISTERS THAT WERE IN MY HAIR, BECAUSE THIS SIDE OF MY HEAD, IT WAS LIKE THREE, FOUR ROWS OF BLISTERS THAT WENT ALL THE WAY DOWN. SO I HAD TO USE MY FINGERS TO COMB THIS SIDE OF MY HAIR. >> DID YOU HAVE ANY BLISTERS ON THE OTHER SIDE OF YOUR HEAD? >> NOPE. JUST THE ONE SIDE. I WAS SURPRISED WHEN I FOUND OUT THAT I HAD SHINGLES THAT IT WAS ON MY FACE, BUT I DID FIND OUT THAT A LOT OF MEDICATION CAN BRING OUT THE SHINGLES VIRUS, AND STRESS. I WAS ON BOTH. SO I DON'T KNOW WHICH ONE WROUGHT THE SHINGLES ON. >> YOU DON'T HAVE TO TELL ME WHAT IT WAS, BUT WERE YOU TAKING MEDICATION THAT SUPPRESSED YOUR IMMUNE SYSTEM AT THE TIME? >> I THINK IT -- YEAH, I THINK IT WAS. I MEAN, I WAS HURTING SO BAD, I DIDN'T ASK A WHOLE LOT OF QUESTIONS. IT WAS LIKE GIVE ME THE DRUGS SO I CAN START TAKING THEM NOW TO GET RID OF THIS PAIN, BECAUSE THE PAPER I PAIN IS THAT SEVERE. I DON'T KNOW HOW STRONG MINDED PEOPLE ARE AND WHATNOT, BUT IF YOU EVER GET SHINGLES AND I DON'T CARE HOW OLD YOU ARE, DO NOT BE ALONE. JUST DON'T BE ALONE. SOMEBODY YOU CAN YELL AT, YOU CAN CRY WITH, BUT JUST DON'T BE ALONE BECAUSE IT WILL SET YOU CRAZY, BECAUSE YOU CAN'T DO ANYTHING ABOUT THE PAIN EXCEPT WAIT. >> WHAT DID YOUR DOCTOR TREAT WITH YOU? >> PILLS. MEDICATION. THREE TIMES A DAY. I HAVE IT IN MY BAG. I COULDN'T PRONOUNCE IT FOR YOU. >> SOMETHING CALLED VALTREX OR -- >> VALVC -- >> THE TRADE NAME IS VALTREX. AND THE GENERIC IS VALACYCLOVIR. >> BUT IT WORKS. >> DID YOU TAKE ANYTHING FOR PAIN? >> NO. AT FIRST I TOOK THE TYLENOL BECAUSE THE MEDICATION THAT I'M ON, EXTRA-STRENGTH TYLENOL IS THE ONLY THING I CAN HAVE. NO, IT WAS A WASTE. >> SO EXTRA-STRENGTH TYLENOL, 500 MILLIGRAMS, DIDN'T TOUCH IT? >> NO, DIDN'T HELP AT ALL. YOU DIDN'T EVEN KNOW YOU TOOK TYLENOL. THAT'S JUST HOW GREAT THE PAIN IS. THE ONLY WAY I CAN DESCRIBE IT IS THE PAIN WAS UNDER THE SKIN. SO ANYTHING YOU DID ON THE SURFACE, IT WASN'T GONNA WORK. >> DID YOUR DOCTOR OFFER YOU ANY OTHER TYPES OF MEDICATION FOR PAIN? >> NO, AND I REALLY DIDN'T ASK. >> SOUNDS LIKE YOU HAD A VERY CHALLENGING TIME THERE. SO GLAD YOU'RE BETTER. >> BUT I STILL FEEL LIKE I'M FORTUNATE BECAUSE PEOPLE HAVE IT FOR MONTHS. >> THAT'S RIGHT. >> I WAS JUST A WEEK. >> WE'LL TALK ABOUT THAT A LITTLE MORE. SO WOULD YOU MIND ANSWERING QUESTIONS FROM THE AUDIENCE IF THEY HAVE ANY? >> NO. >> DOES ANYBODY HAVE QUESTIONS FOR SANDRA? >> DID YOU HAVE CHICKEN POX? >> YES, AS A CHILD. AND I DID NOT THINK THAT I WOULD GET SHINGLES. BEEN HEARING ABOUT IT, READING ABOUT IT, COMMERCIALS ON TV, IT JUST NEVER REGISTERED. LET IT REGISTER IN EVERYBODY'S MIND NOW, IF YOU HAD THE CHICKEN POX, IF YOU'RE CONSULTING A DOCTOR, IF YOU'VE HAD THE CHICKEN POX, GET THE VACCINE. MY DAUGHTER IS 24. I HAD HER GO TO HER DOCTOR AT 24 AND SHE HAD A MILD CASE OF CHICKEN POX ALL OVER HER FACE, AND THAT WAS IT. HER TEMPERATURE WAS 100. IF IT GOT THAT HIGH. HER DOCTOR SAID NO, SHE WASN'T CONCERNED, THE DOCTOR WASN'T CONCERNED AT 24 THAT SHE SHOULD GET THE VACCINE, THEN I WASN'T EITHER. I HAVE A DOCTOR'S APPOINTMENT IN MARCH WITH MY DERMATOLOGIST, AND I WANT TO MAKE SURE THAT MY SYSTEM IS CLEAR OF SHINGLES BECAUSE I AM GOING TO GET THE SHINGLES VACCINE, I UNDERSTAND I CAN GET SHINGLES TWO MORE TIMES DISWHR. SO WE'LTIMES.>> WE'LL TALK MORE AB OUT THAT, OUR GOAL IS TO HELP EVERYBODY UNDERSTAND HOW SHINGLES HAPPENS AND CAN IT HAPPEN AGAIN, WHO SHOULD GET THE VACCINE, SO THAT'S ALL IN OUR TALK. I HOPE YOU CAN STAY AND LISTEN TO US. ANY QUESTIONS BEFORE WE FINISH? >> OKAY. THANK YOU. >> THANK YOU SO MUCH FOR SHARING YOUR STORY. THANK YOU. [APPLAUSE] >> OKAY. WE'RE GOING TO DIVIDE THE TALK HERE INTO PARTS. I'M GOING TO BE TALKING A LITTLE ABOUT WHAT SHINGLES IS, AND THE IMMUNE RESPONSE TO SHINGLES, THEN DR. DROPULIC WILL TELL US ABOUT HOW WE TREAT SHINGLES AND HOW WE TRY TO PREVENT SHINGLES. THE VIRUS THAT CAUSES SHINGLES IS CALLED THE VARICELLA ZOSTER VIRUS. YOU'VE HEARD FROM WIN. THIS IS A VIRUS THAT CAUSES US TO GET CHICKEN POX OR VARICELLA USUALLY WHEN WE'RE VERY YOUNG. YOU CAN SEE HERE A YOUNG CHILD HERE WHO HAS A DISSEMINATED RASH AND THIS RASH IS FROM THE VARICELLA ZOSTER VIRUS. IT AFFECTS THE OROPHARYNX, THE MOUTH, IT AFFECTS THE LYMPHOCYTES THAT ARE AT THE T CELLS, PARTICULARLY CD4 CELLS, AND THE CD4 CELLS TRAVEL THROUGHOUT THE BODY, THEY CAN TRAVEL TO THE SKIP AND YOU CAN SKIN AND YO U CAN GET A RASH, THEY CAN TRAVEL TO DIFFERENT ORGANS AND THEY CAN ALSO TRAVEL TO THE NERVOUS SYSTEM. WHEN THE NERVOUS SYSTEM BECOMES INFECTED WITH THE VIE RU THE VIRUS, IT STAYS IN YOUR NERVOUS SYSTEM FOR THE ENTIRE LIFE. SO ANYBODY THAT'S HAD CHICKEN POX, YOU HAVE THE VIRUS AND THAT CAN REACTIVATE AS YOU GET OLDER, AS WE'LL HEAR ABOUT. SO WHEN THE VIRUS REACTIVATES, ONE GETS A RASH AND THE RASH, AS YOU HEARD FROM WIN, CAN FREQUENTLY BE SORT OF A BELT-LIKE RASH AROUND THE THORAX, SHOWN HERE, AND THE RASH ITSELF IF YOU LOOK ON THE BOTTOM LOOKS JUST LIKE THE RASH OF CHICKEN POX, BUT IT'S DEFINED IN JUST A ONE -- WHAT'S CALLED A DERMATOME, INNERVATED BY A NERVE AS OPPOSED TO CHICKEN POX, WHICH IS SPREAD THROUGHOUT THE ENTIRE SKIN. SO THIS SLIDE JUST SHOWS AGAIN DURING THE CHICKEN POX, THE VIRUS CAN SPREAD IN THE BLOOD AND INFECT THE DORSAL ROOT GANGLIA, AND EACH OF THEM WILL INNERVATE A DIFFERENT PART OF THE SKIN. THE VIRUS CAN ALSO INFECT THE SKIN, SHOWN HERE, AND CAN TRAVEL UP THE NERVE AND ALSO INFECT THE DORSAL ROOT GANGLIA. BUT THIS IS THE SITE WHERE THE VIRUS IS DORMANT OR LATENT FOR THE REST OF YOUR LIFE. IF YOU'RE UNLUCKY, THE VIRUS CAN REACTIVATE FROM THE DORSAL ROOT GANGLIA, COME DOWN THE NERVE AND THEN CAUSE THE RASH OF ZOSTER, AND AGAIN, THE RASH IS LOCALIZED TO THE INDIVIDUAL DORSAL ROOT BEGAN DPLEE A WHERE IT REACTIVATED SO IT'S USUALLY JUST A PATCH OF SKIN. THERE ARE DORSAL ROOT GANGLIA ON EACH SIDE OF THE SPINE SO ONE TYPICALLY GETS A RASH ON ONE SIDE OF THE BO DEE NOT BOD SITES, AND THAT'S A VERY IMPORTANT DISTINGUISHING FACTOR FOR THE DOCTOR TO KNOW THAT IT'S SHINGLES AND NOT SOMETHING ELSE. NOW, SEVERAL YEARS AGO IN OUR LABORATORY, WE LOOKED AT GANGLIA FROM INDIVIDUALS WHO DIED FOR OTHER REASONS, AND THERE WERE ACTUALLY 10 INDIVIDUALS WHO DIED, SOME JUST FROM OLD AGE. WE TOOK OUT THE DORSAL ROOT GANGLIA, HERE IS A CROSS-SECTION OF ONE OF THE GANGLIA, AND YOU CAN SEE THESE ROUND THINGS HERE, WHICH ARE ACTUALLY INDIVIDUAL NEURONS, AND USING LASER MICRO CAPTURE DISSECTION, YOU CAN CAPTURE INDIVIDUAL NEURONS AND PUT THEM ON A SLIDE. THIS NEURAL ON IS NO LONGER -- IS NOW GONE BECAUSE IT'S BEEN PUT ON A SEPARATE SLIDE. THEN CAN YOTHEN YOU CAN TAKE THESE INDIVIDUAL NEURONS AND DETERMINE WHETHER THE SHINGLE VIRUS IS IN THOSE NEURONS. CAN YOU SEE WE HAD TO LOOK AT OVER 1700 NEURONS IN THIS STUDY BEFORE WE LET HER FINISH THE STUDY, YOU CAN SEE THAT APPROXIMATELY 4% HAD VARICELLA ZOSTER VIRUS IN THEM. THE AVERAGE NEURON THAT HAD THE VARICELLA ZOSTER VIRUS IN IT HAD ABOUT SEVEN COPIES IN EACH NEURON. SO WE CAN ACTUALLY LOOK AND SEE, AGAIN, HOW MANY NEURONS ARE INFECTED AND WHAT THE COPY NUMBER PER NEURON IS. SO AGAIN YOU HEARD FROM WIN, HERPES ZOSTER GETS ITS NAME FROM GIRDLE, THIS IS SORT OF A TYPICAL RASH HERE, AND THE VIRUS WAS FIRST ACTUALLY SEEN ON MARCH 19TH, 1940 FLIEN. 1949. WE HEARD TOM WELLER ACTUALLY IDENTIFIED THE VIRUS, AND HE TOOK CULTURED CELLS, TOOK FLUID FROM A BLISTER WE CALL VESICLE FLUID, PUT IT ON TO THESE CULTURED CELLS, AND THEN STAINED THE CELLS. WHAT YOU CAN SEE ARE INDIVIDUAL CELLS, THESE BLUE AREAS ARE THE NUCLEUS OF THE CELL, AND IN ALMOST ALL THE NUCLEUS, YOU SEE THIS RED AREA, INCLUSION BODY, AND THIS IS WITH THE NEURONS HERE, THE INCLUSIONS STAIN RED, SO EACH ONE OF THESE CELLS HAS VIRUS IN IT HERE. SO IN HIS LAB NOTEBOOK ON MARCH 19TH, HE NOTED THAT HE HAD FOUND EFFECTS CORRESPONDING TO THE SHINGLES OR VARICELLA ZOSTER VIRUS. AS YOU HEARD, HE WENT ON TO WORK WITH OTHER GROUPS, OTHER INDIVIDUALS IN HIS GROUP AND WON THE NOBEL PRIZE FOR POLIO. SO THIS IS AN ELECTRON MICROGRAPH UP WHAT THE VARICELLA ZOSTER VIRUS LOOKS LIKE. YOU SEE A NUCLEIC ACID, WHICH IS A PROTEIN THAT ENCOATS THE DNA, PROTECTS IT, THEN THERE'S AN ENVELOPE AROUND IT, THEN THERE ARE THESE SPIKES THAT HAVE GLYCOPROTEINS ON IT AND THAT'S HOW THE VIRUS ATTACHES TO YOUR CELLS. SO ABOUT 99% OF US OVER AGE 40 HAVE BEEN INFECTED WITH VARICELLA ZOSTER VIE RU WHICH VIRUS, WHICH MEANS WE'RE ALL AT RISK FOR DEVELOPING SHINGLES. EACH YEAR THERE ARE ABOUT A MILLION CASES IN THE UNITED STATES AND UNFORTUNATELY THE RATE OF SHINGLES SEEMS TO BE INCREASING. WE CAN TALK ABOUT THAT LATER, IF THERE ARE QUESTIONS ABOUT THAT, BUT ABOUT 50% OF US, IF WE LIVE TO AGE 85, WILL DEVELOP SHINGLES, AND ABOUT 5% OF US CAN ACTUALLY GET A SECOND CASE OF SHINGLES. SO IT REALLY AFFECTS A LARGE PORTION OF THE POPULATION. THE MAJOR RISK FACTORS FOR GETTING SHINGLES ARE AGE AND THE OLDER YOU ARE, THE MORE LIKELY YOU ARE TO GET SHINGLES. AND PART OF THAT IS BECAUSE IT'S BEEN A LONG TIME SINCE YOU HAD CHICKEN POX, IT'S A LONG TIME SINCE YOUR IMMUNE SYSTEM HAS SEEN THE VIRUS, AND YOUR IMMUNE SYSTEM CAN NO LONGER RECOGNIZE THE VIRUS AS WELL AS WE GET OLDER. SO THE LONGER SINCE YOU HAD YOUR EPISODE OF VARICELLA OR CHICKEN POX, THE MORE LIKELY YOU ARE TO GET SHINGLES. INDIVIDUALS WHO ARE IMMUNE-COMPROMISED, PARTICULARLY THOSE WHO HAVE IMPAIRED WHAT'S CALLED T CELL IMMUNITY, NOT PEOPLE WHO HAVE LOW LEVELS OF ANTIBODIES BUT LOW LEVELS OF T CELLS LIKE TRANSPLANT RECIPIENTS, PEOPLE WITH LEUKEMIA, LYMPHOMA, HIV PATIENTS, THOSE INDIVIDUALS ARE ALSO MORE LIKELY TO GET SHINGLES. AGAIN, THEIR IMMUNITY TO VARICELLA ZOSTER VIRUS, THEIR T CELL IMMUNITY WANES. SO AGE AND IMMUNOCOMPROMISE REDUCE T CELL IMMUNITY AND ALLOW THE VIRUS TO REACTIVATE. SO AS I MENTIONED, THE VIRUS CAN BE LATENT OR DORMANT IN THE DORSAL ROOT GANGLIA, WHICH ARE ALONGSIDE THE SPINE. CAN REACTIVATE ALONG THE NERVE AND RESULT IN A RASH ALONG THE CHEST OR ABDOMEN. IT CAN ALSO BE LATENT IN WHAT'S CALLED THE TRIGEMINAL GANGLIA WHICH IT LIKELY WAS IN OUR PATIENT TODAY OR IN THE FACIAL NERVE HERE. AGAIN, THE VIRUS CAN REACTIVATE ON THE FACE. SO IT TURNS OUT THAT, AGAIN, THE DORSAL ROOT GANGLIA INNERVATE PORTIONS OF THE SKIN, ALONG THE SPINE. ONE OF THE WAY THESE DERMATOMES WERE MAPPED MANY YEARS AGO WAS BY SEEING PATIENTS WITH SHINGLES AND NOTICING THAT THE RASH WAS IN A DIFFERENT -- WAS IN A CERTAIN AREA HERE, AND HE SURMISED THAT THAT'S WHERE THE DORSAL ROOT GANGLIA MUST BE BECAUSE THE VIRUS IS REACTIVATING FROM THAT. SO IT WAS A WAY ACTUALLY TO MAP THE ANATOMY OF THE HUMAN BODY, WHICH I THOUGHT WAS QUITE INTERESTING. SO HERE'S A WOMAN WHO HAS A RASH ON HER BACK HERE, ACTUALLY IN THE DERMATOMES BY THE T1 AND T2 THORACIC DERMATOMES. HERE'S ANOTHER WOMAN WHO HAS A RASH A LITTLE HIGHER UP AS WELL AS ON HER ARM, AND YOU CAN SEE THAT CORRESPONDS TO THE C5 AND C6 DERMATOMES. A GENTLEMAN WITH A RASH ON HIS FACE, CAN YOU SEE IT'S THE LEFT SIDE OF HIS FOR HEAD, THE LEFT SIDE OF HIS NOSE AND INVOLVING THE EYE, AGAIN ON THE B1 DISTRIBUTION OF THE TRIGEMINAL NERVE. SO AS WE HEARD TODAY, THE RASH IS OFTEN -- IT DOES NOT CROSS THE MIDLINE, IT'S JUST ON ONE SIDE OF THE BODY. INDIVIDUALS CAN HAVE A FEW LESIONS OUTSIDE THE DERMATOME, AND THE RASH USUALLY CONTINUES, NEW LESIONS POP UP FOR MAYBE FIVE DAYS TO A WEEK. THESE RASHES START OFF AS JUST BUMPS, THEY EVENTUALLY BECOME FLUID HAD BEE-FILLED BUMPS WHICH ARE VEST KELS, YOU HAVE PUSTULES, PUS INSIDE THOSE AREA, THEN EVENTUALLY THEY BREAK DOWN AND THEY CRUST OVER AND HEAL UP AND IT USUALLY TAKES ABOUT 10 DAYS TO CRUST OVER AND MAYBE TWO WEEKS FOR THE RASH TO REALLY RESOLVE. SOME PATIENTS ACTUALLY DON'T GET A RASH, THEY'LL JUST HAVE PAIN IN THE AREA, AND THAT' THAT CAN BE A VERY DIFFICULT DIAGNOSIS FOR THE DOCTOR TO MAKE. IN ADDITION TO THE RASH, WHAT MANY PEOPLE FEAR IS REALLY THE PAIN ASSOCIATED WITH SHINGLES. TYPICALLY BEFORE THE RASH OCCURS, AS YOU HEARD TODAY, A PERSON CAN HAVE A CHANGE IN SENSATION LIE ITCHING, TINGLING IN THAT AREA, AND THAT CAN MAKE IT VERY DIFFICULT TO TELL THAT IT'S REALLY DUE TO SHINGLES. SOME PATIENTS HAVE HAD A LOT OF PAIN IN THE AREA, IMON TO THE HOSPITAL AND BEEN MISDIAGNOSED AS HAVING ABDOMINAL, CHEST PAIN, HAVING A HEART ATTACK, AND SUDDENLY A RASH ERUPTS IN THAT AREA AND THEN THE DOCTOR REALIZES NO, IT'S NOT A HEART ATTACK, IT'S ACTUALLY JUST SHINGLES CAUSING ABDOMINAL OR CHEST PAIN. THE PAIN CAN RANGE FROM STABBING, BURNING, EXCRUCIATING PAIN, SOME PATIENTS HAVE IT CONTINUOUSLY, SOME EPISODICALLY, SOME PATIENTS WON'T HAVE ANY PAIN, PARTICULARLY YOUNGER INDIVIDUALS. THE OLDER YOU ARE, THE MORE LIKELY YOU ARE TO HAVE PAIN WITH THAT RASH. THE PAIN CAN LAST FOR DIFFERENT PERIODS OF TIME. THIS WAS A STUDY DONE IN INDIVIDUALS ABOUT 56 YEARS OLD, ON MEAN, AND YOU CAN SEE AT ONE MONTH, FOR INSTANCE, ABOUT 55% OF THEM HAD PAIN STILL, ABOUT 5% HAD SEVERE PAIN, BUT UNFORTUNATELY MANY OF THESE INDIVIDUALS HAD RESIDUAL PAIN EVEN AFTER THE RASH HAD RESOLVED RESOLVED. FOR CLINICAL STUDIES, WE SAY AN INDIVIDUAL THAT HAS A RASH -- EXCUSE ME -- THAT HAS PAIN LASTING LONGER THAN THREE MONTHS AFER THE ONSET OF THE RASH HAS A DISEASE CALLED POST HERPETIC NEURALGIA. SO AGAIN, EVEN AFTER THE RASH RESOLVES, INDIVIDUALS CAN HAVE THIS PAIN. SO POST HERPETIC NEURALGIA, PAIN CAN PERSIST FOR MONTHS OR EVEN YEARS. IT'S THOUGHT TO BE DUE TO NERVE DAMAGE CAUSED BY THE SHINGLES VIRUS, AND THE NERVE DAMAGE CAN BE THE NERVES INVOLVED IN THE SKIN OR THE NERVES ACTUALLY GOING EVEN TO THE SPINA SPINAL CORD. MORE COMMON THE OLDER YOU R AND PEOPLE CAN HAVE VERY DIFFERENT KINDS OF PAIN WITH THAT POST HERPETIC NEURALGIA. SOME PEOPLE SAY THAT JUST CLOTHES TOUCHING YOUR SKIN CAN CAUSE JUST AGONIZING PAIN OR A BREEZE ON YOUR CHEEK CAN CAUSE JUST SEVERE, SEVERE PAIN. THAT'S CALLED ALADINEA, A NON-PAINFUL STIMULUS CAUSING PAIN, PEOPLE CAN HAVE PARESTHESIAS WITH BURNING AND TINGLING OR CONTINUOUS NEWERPATHIC PAIN, AND IT REALLY CAN BE QUITE SEVERE. SO HOW DOES ZOSTER, HOW DOES POST HERPETIC NEURALGIA AFFECT PEOPLE'S LIVES? WELL, IT CAN -- PEOPLE CAN HAVE FATIGUE, WEIGHT LOSS, LOSS OF APPETITE, PHYSICAL ACTIVITY, PEOPLE CAN HAVE DIFFICULTY SLEEPING AT NIGHT, ANXIETY, DEPRESSION, SUICIDAL IDEATION, THEY CAN BECOME VERY INTROVERTED AND STOP INTERACTING WITH PEOPLE AND IT CAN REALLY BE VERY TRAUMATIC AND REALLY MAKE LIVES MISERABLE. MY FATHER WAS A VERY ACTIVE WORKING PERSON, DEVELOPED SHIP GELSHINGLES AND POST HERPETIC NEURALGIA. HE HAD PAIN FOR OVER A YEAR AND ALMOST DIDN'T SLEEP FOR A YEAR, SUBSEQUENTLY RETIRED, AFTER A YEAR IT FINALLY RELENTED, BUT HE SAID HE WOULDN'T WISH IT ON HIS WORST ENEMY. SO AGAIN THE RISK FACTORS FOR POST HERPETIC NEURALGIA, THE OLDER YOU ARE, THE MORE LIKELY SHINGLES CAN DEVELOP INTO POST HERPETIC NEURALGIA. IT'S RARE IN INDIVIDUALS UNDER 40. FOR INDIVIDUALS WHO HAVE THE MOST SEVERE PAIN OR THE MOST SEVERE RASH, THAT'S PROBABLY ASSOCIATED WITH THE MOST NERVE DAMAGE, AND THOSE ARE THE INDIVIDUALS THAT ARE HIGHEST RISK FOR GETTING POST HERPETIC NEURALGIA. INTERESTINGLY IMMUNE CROW MIEZ IS NOT REALLY A RISK FOR POST HERPETIC NEURALGIA. IT IS FOR SHINGLES. SO POST HERPETIC NEURALGIA, THERE'S 100,000 TO 200,000 CASES PER YEAR. ABOUT 10% OF ZOSTER PATIENTS WILL HAVE PAIN THAT LASTS MORE THAN 90 DAYS. 20% WILL HAVE PAIN LASTING MORE THAN 30 DAYS. AND HERE THIS SHOWS THE RATES OF BOSS ZOSTER, SHOWN IN GRAY HERE, AND POST HERPETIC NEURALGIA. THE OLDER YOU ARE, THE MORE LIKELY TO GET SHINGLES AND THE MORE LIKELY TO RESULT IN POST HERPETIC NEURALGIA. SO THERE ARE A NUMBER OF NEUROLOGIC COMPLICATION OF ZOSTER. PEOPLE CAN HAVE WHAT'S CALLED BELL'S PALSY, WHERE YOU HAVE DROOPING OF THE SIDE OF THE FACE, UNILATERAL FACIAL PARALYSIS, AND THAT'S DUE TO REACTIVATION OF THE VIRUS IN ONE OF THE CRANIAL NERVES. IF THE VIRUS REACTIVATES IN A DIFFERENT AREA OF THE CRANIAL NERVE, YOU CAN HAVE VESICLES IN YOUR EAR WITH NUMBNESS OF THE TONGUE, AGAIN, WEAKNESS OF THE FACIAL MUST ELSE. MUSCLES. OFTENTIMES THESE DO RESOLVE OVER TIME BUT IT CAN BE REALLY MISERABLE WHEN YOU HAVE IT. ANOTHER CRANIAL NERVE CAN BE INVOLVED, YOU CAN HAVE HEARING IMPAIRMENT, PEOPLE CAN HAVE MENINGITIS, GILLIAN B BARRE, PARALYSIS KNOWN AS TRANSVERSE MY LIGHTS. IF THE MYELITIS. IF THE VIRUS AFFECTS THE CRANIAL ARTERIES, IT CAN CAUSE VASCULITIS, ARTERIES GET VERY NARROWED, PREEM CAN ARE A STROKE, OR A TRAN TRANSISCHEMIC EVENT, BUT IT CAN BE A VERY SEVERE DISEASE AS A CAUSE OF STROKE EVEN. THEN EYE COMPLICATIONS ARE ALSO SEEN IN PATIENTS WITH ZOSTER. PARTICULARLY FOR PEOPLE WHO HAVE A RASH, MENTIONED WITH THE B1 DISTRIBUTION INVOLVING THE SIDE OR THE TIP OF THE NOSE. REALLY ANY PART OF THE EYE CAN BE INVOLVED. 15% OF INDIVIDUALS WILL GET -- WITH ZOSTER CAN GET ZOSTER INVOLVING THE EYE. IT CAN AFFECT THE CORNEA, THE SURFACE OF THE EYE, IT CAN AFFECT THE INTERIOR OF THE EYE, UVEITIS, IT CAN AFFECT THE RETINA, THAT WE USE FOR VISION, AND IT CAN ALSO CAUSE GLAUCOMA. SEVERAL YEARS AGO, I SAW A PERSON WHO PRESENTED WITH PROBLEMS WITH VISION, HIS DOCTOR SAID DON'T WORRY ABOUT IT, I RECOMMEND YOU GO TO AN OPHTHALMOLOGIST, AND HE ACTUALLY HAD SO MUCH INFLAMMATION OF THE EYE THAT IT WAS BLOCKING THE PATH OF FLUID IN HIS EYE, INCREASED PRESSURE IN HIS EYE, AND HE HAD TO BE TREATED FOR GLAUCOMA, OTHERWISE HE WOULD HAVE LOST VISION IN THE EYE. SO IT'S VERY IMPORTANT IF ONE HAS EYE INVOLVEMENT TO SEE THEIR EYE DOCTOR, BECAUSE THERE ARE SOMETIMES SPECIALIZED TREATMENTS THAT AN EYE DOCTOR WILL PROVIDE. OTHER COMPLICATIONS, THE RASH CAN BECOME INFECTED WITH BACTERIA, PEOPLE CAN HAVE A LOT OF ITCHING EVEN AFTER THE RASH IS GONE. ABOUT 3% OF PATIENTS WITH ZOSTER ARE HOSPITALIZED EITHER FOR THE NEUROLOGIC COMPLICATIONS OR FOR THE OCULAR COMPLICATIONS. AS WE HEARD TODAY, THE VIRUS CAN BE TRANSMITTED TO SUSCEPTIBLE CHIRP. IF YOU'VE HAD THE CHICKEN POX VACCINE YOU SHOULDN'T GET ZOSTER FROM SOMEONE, BUT AN INFANT THAT'S NEVER SEEN THE VIRUS, THEY CAN GET IT FROM SHINGLES, AND AGAIN, THE VIRUS IS LESES TRANSMISCIBLE FROM SOMEBODY WITH SHINGLES, AS SOMEBODY WHO HAS VARICELLA OR CHICKEN POX. NOW, WHAT I'VE MENTIONED BEFORE IS WHAT HAPPENS IN PEOPLE WHO ARE -- HAVE A NORMAL IMMUNE SYSTEM, BUT UNFORTUNATELY WE SOMETIMES SEE INDIVIDUALS WHO HAVE HAD A BONE MARROW TRANSPLANT, A PATIENT WHO HAS HIV OR SOMETHING LIKE THAT, AND THOSE PEOPLE CAN HAVE EVEN A WORSE CASE WITH SLIN GELS. IN THOSE INDIVIDUALS, WHEN THE VIRUS REACTIVATES, INSTEAD OF JUST GOING ALONG A NERVE, THE VIRUS CAN REACTIVATE IN THE BLOOD AND ONE CAN GET VIRUS IN THE BLOOD OR VIREMIA. INSTEAD OF GETTING JUST A RASH THAT'S LOCALIZED TO ONE SORT OF STRIP ON THE BODY, THOSE INDIVIDUALS CAN GET A DISSEMINATED RASH THAT LOOKS IDENTICAL TO CHICKEN POX. AGAIN THE VIRUS IS SPREAD IN THE BLOOD JUST LIKE IT DOES DURING CHICKEN POX AND THOSE INDIVIDUALS CAN GET VERY ILL AND DIE FROM ZOSTER. THOSE INDIVIDUALS FREQUENTLY HAVE LESIONS THAT FORM FOR MANY WEEKS, MUCH LONGER THAN YOU WOULD IN A NORMAL HOST, HEALING CAN TAKE LONGER, THI CAN GET THIS GENERAL RISED RASH BUT THEY'RE ALSO MORE LIKELY TO GET COMPLICATIONS WITH VIRAL PNEUMONIA, VIRUS INFECTING THE LIVER WITH HEPATITIS, VIRUS IN THE BRAIN AND ENCEPHALITIS. SO PATIENTS THAT ARE VERY IMPORTANT FOR THEM TO GET MEDICAL CARE TO GET TREATMENT. WE'VE SEEN PATIENTS HERE WITH HIV, THIS WAS A PATIENT I SAW A NUMBER OF YEARS AGO, WHO THIS WARTY-LIKE ERUPTION BUT WHEN IT WAS BIOPSIED, THERE WAS VARICELLA ZOSTER VIRUS IN THE TISSUE HERE. IT WAS AN UNUSUAL RASH ASSOCIATED WITH ZOSTER. PATIENTS WITH HIV CAN GET NECROSIS OF THE RETINA, AND THEY CAN ACTUALLY GET CHRONIC ZOSTER, WHICH DOESN'T REALLY GO AWAY, IT JUST PERSIST, DESPITE THERAPY. WE'VE ALSO SEEN A BONE MARROW TRANSPLANT OR STEM CELL TRANSPLANT PATIENTS THAT WILL REACTIVATE INTERNALLY IN THE SILL YAK GANGLIA WHICH INNERVATES THE G.I. TRACT, THOSE INDIVIDUALS CAN GET INFLAMMATION OF THE PANCREAS OR ABDOMINAL PAIN. I SAW A PATIENT IN THE INTENSIVE CARE UNIT WHO HAD ABDOMINAL PAIN, NO RASH AT ALL, AND THE WAY IT WAS DIAGNOSED UNFORTUNATELY WAS THE NURSE THAT TOOK CARE OF THE PATIENT HAD NEVER HAD CHICKEN POX, BECAME INFECTED WITH CHICKEN POX. SO THIS IS VERY DIFFICULT TO DIAGNOSIS, ANDIAGNOSE, AND IF IT'S NOT DIAGNOSED PARTICULARLY IN AN IMMUNOCOMPROMISED PATIENT, IT CAN BE FATAL. NOWADAYS WE CAN SAMPLE THE BLOOD AND DETECT THE VIRUS IN THE BLOOD. THIS WAS AN HIV PATIENT I SAW A NUMBER OF YEARS AGO. AND YOU CAN SEE THERE'S A LEAGUES IN THE EYE HERE DUE TO VARICELLA ZOSTER VIRUS. AND THE PATIENT ALSO HAD LESIONS IN THE BRAIN DUE TO THE VIRUS. SO AGAIN, THESE IMMUNOCOMPROMISED PATIENTS CAN BE VERY ILL. SO THE IMMUNOLOGY OF ZOSTER, ZOSTER PATIENTS TURN OUT TO HAVE NORMAL LEVELS OF ANTIBODY TO VARICELLA ZOSTER BUT THEY HAVE REDUCED T CELL IMMUNITY. ZOSTER IS DUE TO WEAKENING OR REDUCTION OF THE VIRUS-SPECIFIC T CELL IMMUNITY, NOT DUE TO LACK OF ANTIBODIES. SO OVER TIME AS WE AGE, IF WE LOOK AT THE CELLULAR RESPONSE TO VARICELLA ZOSTER VIRUS, EITHER BY A SKIN TEST IN WHICH A DOCTOR CAN PUT VARICELLA ZOSTER VIRUS APT GENERAL OANTIGEN ON THE SKIN, OR YOU C AN TAKE OUT BLOOD AND LYMPHOCYTES THAT PROLIFERATE IN RESPONSE TO THE VIRUS, AS WE AGE, THE CELLULAR IMMUNITY TO THE VIRUS GOES DOWN AND THAT MEANS WE'RE SUSCEPTIBLE TO REACTIVATION, MORE SUSCEPTIBLE TO ZOSTER. THE MODEL THAT'S BEEN PROPOSED IS IF YOU LOOK HERE, THIS IS THE LEVEL OF CELLULAR IMMUNITY TO VARICELLA ZOSTER VIRUS, AN INDIVIDUAL BECOMES INFECTED WITH CHICKEN POX AND THE IMMUNE SYSTEM RESPONDS TO THE CHICKEN POX, THE T CELLS INCREASE THAT ARE SPECIFIC FOR VARICELLA ZOSTER VIRUS INCREASE IN NUMBER, THEY CAN WAX AND WANE OVER TIME F1 GETS EXPOSED TO A CHILD WITH VARICELLA WHICH IS LESS COMMON NOW THAT WE HAVE A VARICELLA VACCINE, THE T CELL RESPONSE CAN INCREASE. AGAIN, OVER TIME, THE BODY HASN'T SEEN VARICELLA, THE RESPONSE GOES DOWN, CAN YOU HAVE SUBCLINICAL REACTIVATIONS, WHERE YOU DON'T GET THE SHINGLES BUT THE IMMUNE SYSTEM GETS PHILIPPOUSSISED AND SEE THE VIRUS, BUT EVENTUALLY AS WE AGE, MANY OF US, THE CELLULAR IMMUNITY WILL GO BELOW A CERTAIN THRESHOLD AND THE VIRUS WILL REACTIVATE AND WE WILL GET SHINGLES, AND THIS WILL RESULT IN SYMPTOMS. WHAT YOU'LL HEAR DR. DROPULIC MENTION IS WE HAVE A VACCINE NOW WHICH, LIKE ZOSTER, CAN BOOST THE IMMUNE SYSTEM AND RESET THE IMMUNE SYSTEM AND THE IDEA IS THAT THE SHINGLES VACCINE CAN RESET THE IMMUNE SYSTEM SO THAT YOU'RE LESS LIKELY TO GET SHINGLES. SO FINALLY THE DIAGNOSIS OF ZOSTER, USUALLY THE DOCTOR DOES NOT NEED TO DO ANY BLOOD TESTS, USUALLY JUST BY LOOKING AT THE PATIENT F THEY HAVE A TYPICAL RASH ONLY ON ONE SIDE OF THE BODY, IT'S USUALLY LOCALIZED TO ONE OR TWO DERMATOMES ASSOCIATED WITH PAIN, THAT'S ENOUGH TO MAKE A DIAGNOSIS OF ZOSTER. THERE'S SOME PATIENTS WHOEVER WHO MAY NOT HAVE A RASH, MAY HAVE AN ATYPICAL CASE AND WHAT YOU CAN DO IS SCRAPE THE LESIONS LESIONS, YOU CAN DO WHAT'S CALLED A PCR REACTION AND DETECT VIRAL -- OR IF ONE HAS A PERSON WITH BAD CENTRAL NERVOUS SYSTEM DISEASE, ONE CAN DO A SPINAL TAP, TAKE THE SPINAL FLUID, AND DR. DROPULIC AND I ARE OFTEN FREQUENTLY CONSULTED FOR INDIVIDUALS WHO HAD, QUOTE, RECURRENT ZOSTER. MULTIPLE EPISODES OF ZOSTER. AND MOST OF THESE PATIENTS ACTUALLY DON'T HAVE RECURRENT EPISODES OF ZOSTER, THEY HAVE RECURRENT EPISODES OF HERPES SIMPLEX VIRUS WHICH CAN MASQUERADE AND LOOK LIKE ZOSTER. THESE INDIVIDUALS HAD FREQUENT RECURRENCES AS I MENTIONED, MOST PEOPLE ONLY HAVE ONE CASE OF ZOSTER IN THEIR LIFETIME. SO I THINK WHAT WE'LL DO IS MOVE ON TO HOW WE TREAT AND HOW WE PREVENT ZOSTER, AND WE'LL HAVE DR. DROPULIC TELL US ABOUT THAT, THEN WE'LL OPEN IT UP FOR QUESTIONS. [APPLAUSE] >> I WAS NOT AN INVESTIGATOR IN THE SHINGLES VACCINE TRIAL BUT IN OUR LABORATORY, WE DO A STUDY ON HERPES SIMPLEX -- WE HAVE A 2 VACCINE TRIAL THAT'S ONGOING, A PHASE 1. SO THE GOALS OF ANTIVIRAL THERAPY FOR HERPES ZOSTER IS TO DECREASE THE SEVERITY AND DURATION OF THE PAIN CAUSED BY THE ACUTE NEURITIS, SO THIS IS THE INFLAMMATION CAUSED BY THE VIRUS TRANSVERSING DOWN FROM THE SKIN. SO THAT INFLAMMATION OF THAT NERVE WHERE THE VIRUS IS REPLICATING IS CAUSING A LOT OF PAIN. TO PROMOTE MORE RAPID HEALING OF THE SKIN LEAGUES, T LESIONS, TO PREVENT NE W LEAGUES FROM FORMING AND TO REDUCE VIRAL SHEDDING SO REDUCE POSSIBILITY OF TRANSMITTING THIS INFECTION. THESE HAVE BEEN SHOWN TO BE EFFECTIVE IN CLINICAL TRIALS. THEY'RE QUITE WELL TOLERATED. THEY DIFFER IN TERMS OF THEIR BIOAVAILABILITY. THE OLDER DRUG IS THE ACYCLOVIR, WE HAVE TO GIVE THOSE DRUGS MORE FREQUENTLY, FIVE TIMES DAILY, BUT THESE HAVE BEEN REPLACED BY NEWER MEDICATIONS WHICH IS VERY WELL ABSORBED AND GIVES THREE TO FIVE TIMES HIGHER LEVEL OF ANTIVIRAL DRUG ACTIVITY OF ACYCLOVIR, AND IT'S ONLY ADMINISTERED THREE TIMES DAILY. AND THE THESE DRUGS ARE QUITE WELL TOLERATED. THE MOST COMMON SIDE EFFECT IS MALAISE, AND WITH THE OTHERS IT'S NAUSEA AND HEADACHE. INTEREST ITHERE IS CLINICAL TRIAL EVIDENCE FOR THE EFFICACY OF THESE ANTIVIRALS. THEY DO INDEED HASTEN THE RESOLUTION OF LESIONS, THEY REDUCE FORMATION OF NEW LESIONS, THEY REDUCE VIRAL SHEDDING AND ALSO DECREASE THE SEVERITY OF THE ACUTE PAIN. HOWEVER, THERE'S NO EVIDENCE THAT THEY REDUCE THE INCIDENCE OF POST HERPETIC NEURALGIA, WHICH IS PROBABLY THE MOST DEBILITATING COMPLICATION OF SHINGLES. AS YOU HEARD FROM OUR PATIENT, SHE COULDN'T TAKE FOR SOME REASON MEDICATIONS OTHER THAN ACETAMINOPHEN, BUT SHE WAS VERY HAPPY TO BE TAKING WHAT SOUNDS LIKE -- PATIENTS MOST LIKELY TO BENEFIT FROM APT VIRAL THERAPY FOR HERPES ZOSTER ARE PEOPLE 50 YEARS AND OLD E AND THAT'S BECAUSE THEY HAVE MORE SEVERE DISEASE, PATIENTS WITH MODERATE TO SEVERE PAIN AT THE ONSET OF SHINGLES, PATIENTS WITH A SEVERE RASH WITH LARGE NUMBERS OF LESIONS AND PATIENTS WHOSE FACE OR EYES ARE INVOLVED AND WHO HAVE OTHER COMPLICATIONS. SO TO PREVENT A COMPLICATION, WE USE ANTIVIRAL THERAPY IN THESE PATIENTS. IMMUNOCOMPROMISE THE PATIENTS WHO HAVE SEVERE DEBILITATING DISEASE INCLUDING THE CENTRAL NERVOUS SYSTEM, DEFINITELY USE ANTIVIRAL THERAPY IN THESE PATIENTS. USUALLY IN IMMUNOCOMPROMISED HOST, THEY RELY ON THE INTRAVENOUS ADMINISTRATION OF ACYCLOVIR IN ORDER TO GET SUSTAINED LEVELS OF DRUG, SUSTAINED ACTIVITY, TO MOST EFFECTIVELY TREAT THEIR SEVERE INFECTION, CAUTIOUS WITH THE RENAL INSUFFICIENCY BUT IF IT'S ADMINISTERED SLOWLY EVERY ONE TO TWO HOURS, WE DON'T USUALLY ENCOUNTER THIS COMPLICATION. -- WHICH WE DON'T ENCOUNTER USUALLY IN THE NORMAL HOST BUT WE DO ENCOUNTER IN THESE IMMUNOCOMPROMISED HOARS. IMMUNOCOMPROMISED HOSTS. THAT IS NOT FDA-APPROVED, MUCH MORE SIGNIFICANT SIDE EFFECTS INCLUDING RENAL I INSUFFICIENCY, NAUSEA, VOMITING, DECREASED WHITE CELL COUNT, GRAN LOCI TOE PENA. SO THE CHALLENGE IS WHEN SOMEBODY PRESENTS WITH SHINGLES TO TROAT THEIR PAIN, SO THEY TREAT THEIR P AIN. PAIN DERIVED FROM THE NERVOUS SYSTEM BEING AFFECTED CAN BE VERY CHALLENGING. WHAT EXPERTS USUALLY RECOMMEND IS WHEN SOMEBODY HAS MILD PAIN TO USE NON-OPIOID ANALGESICS WITH THINGS LIKE ACETAMINOPHEN OR TRADE NAME TYLENOL OR NONSTEROIDAL ANTI-INFLAMMATORY AGENTS LIKE IBUPROFEN OR MOTRIN OR NA PROX EP. IF THE PAINAPROXEN. IF THE PAIN IS MORE SEVERE, ONE CAN USE MILD NON-OPIOID ANALGESICS, HOWEVER, IF THE PAIN IS MORE SEVERE, ONE MAY HAVE TO USE DRUGS, MEDICATIONS LIKE OXYCODONE. SO ONE HAS TO BASE IT ON HOW THE PATIENT FEELS, HOW SEVERE THEIR PAIN IS, BUT OUR GOAL IS TO ALLEVIATE SYMPTOMS UNTIL THE PATIENT IS COMFORTABLE. SECONDLY, IF THE SYMPTOMS ARE NOT RESPONDING TO THESE ANALGESICS, WE EMPLOY OTHER MEDICATIONS, ANTICONVULSANTS WHICH HAVE ACTUALLY BEEN FDA-APPROVED FOR THE TREATMENT OF NEUROPATHIC PAIN AND CAN BE QUITE EFFECTIVE IN THE CIRCUMSTANCE, AS WELL AS ANTI-DEPRESSANTS, NOR TRIP TA LEAN. ONE CAN USE A COMBINATION OF THESE MEDICATIONS DEPENDING HOW THE PATIENT IS RESPONDING. PREDNISONE, CORTICOSTEROIDS ARE MORE CONTROVERSIAL. THESE SHOULD BE AVOIDED IN PATIENTS WHO HAVE CERTAIN CONDITIONS LIKE DIABETES, HYPOTENSION, OSTEOPOROSIS, BUT THAT WOULD REQUIRE LONG TERM TREATMENTS TO HAVE AN EFFECT ON THAT, SO WE ALWAYS EE STRA EVALUATE THE ENTIRE MEDICAL HISTORY, WE ASSESS WHAT MEDICATIONS THE PATIENT IS ALREADY TAKING TO DETERMINE WHAT STRATEGY MAY BE EMPLOYED IN A PARTICULAR PATIENT. BUT ESPECIALLY -- WE USE CORTICOSTAR OIDZ HAS BEEN ASSOCIATED WITH MORE SEVERE SIDE EFFECTS AND SECONDARY BACTERIAL INFECTIONS, SO WE TRY TO AVOID THAT. LASTLY SOME MAY -- BY USING TOPICAL THERAPIES SUCH AS A LIDOCAINE PATCH, WHICH SHOULD BE APPLIED ON INTACT SKIN. NOT ON TO THE RASH. A LITTLE MORE ABOUT THE USE OF GLUCOCORGLUCOCORTICOID SES, SOME RANDOMIZED CONTROLLED TRIALS HAVE SHOWN A REDUCTION IN ACUTE PAIN, IMPROVED PERFORMANCE OF ACTIVITIES OF DAILY LIVING, HOWEVER, THERE HAS BEEN META-ANALYSIS WHERE THEY LOOKED AT FOUR PLACEBO-CONTROLLED TRIALS, THEY DIDN'T FIND THESE OUTCOMES WERE INDEED TRUE. STUDYS HAVE NOT SHOWN A REDUCTION IN INCIDENCE OF POST HERPETIC NEURALGIA. RARELY WE DO USE THEM WHEN WE ENCOUNTER A CASE OF HERPES -- THE VAST QUEUE LIGHTS THA VASCULITIS OR BE LL'S PALSY COMMONLY ALONG WITH ANTIVIRAL TREATMENT TREAT THESE INFECTIONS IN THE CENTRAL NERVOUS SYSTEM IN ORDER TO AT THE SAME TIME DECREASE THE INFLAMMATION AND DECREASE COMPLICATIONS AND SYMPTOMS. I MENTIONED ALREADY ABOUT AVOIDING USE OF STEROIDS IN PATIENTS WHO HAVE BEEN SUBJECT TO COMPLICATIONS FROM USE OF STEROIDS. TREATMENT OF POST HERPETIC NEURALGIA CAN BE QUITE CHALLENGING. AS YOU'VE HEARD, PATIENTS CAN HAVE PAIN FOR A PROLONGED PERIOD OF TIME, NEUROPATHIC PAIN, NOTORIOUSLY DIFFICULT TO TREAT. LISTED HERE ARE MEDICATIONS THAT HAVE BEEN APPROVED FOR TREATMENT OF POST HERPETIC NEURALGIA, MAINLY THE ANTICONVULSIVE AND TRY CYCLIC ANTI-DEPRESSANTS HAVE BEEN APPROVED FOR NEUROPATHIC-TYPE PAIN AND ARE COMMONLY EMPLOYED TO TRY TO PROVIDE SOME RELIEF TO THESE PATIENTS OF THE DEBILITATING COMPLICATIONS OF ZOSTER. THEY CAN BE USED INDEPENDENTLY SO OFTEN EXPERTS RECOMMEND STARTING WITH THE TRY CYCLIC ANTIDEPRESSANTS INITIALLY AND THEN IF THAT DOESN'T WORK OR PERHAPS ADDING THE ANTICONVULSANTS ON BOARD. THE THIRD LINE OF POSSIBLE TREATMENT WE RESERVED THAT LATER TO OPIOIDS BECAUSE OF THE CONCERNS FOR ADDICTION, SO THIS COMES UP LATER. ALSO WITH OUR TOPICAL THERAPIES LIKE LIDOCAINE AND CAPSAICIN, LIDOCAINE NEEDS TO BE APPLIED TO INTACT SKIN. CAPSAICIN IS TRICKY BECAUSE IT HAS TO BE APPLIED SEVERAL TIMES A DAY FOR 90 MINUTES AND TAKEN OFF, PEOPLE COMPLAIN OF THE BURNING SENSATION, AND REDNESS ON THE SKIN, SO IT'S A DIFFICULT TREATMENT TO FOLLOW SOMETIMES. BECAUSE IT IS SO CHALLENGING, OFTEN TIMES WE SEEK THE ASSISTANCE OF PAIN SPECIALISTS WHEN WE HAVE A PATIENT WHO HAS POST HERPETIC NEURALGIA WHO USE THE STANDARDIZED APPROACH FOR TREATING CHRONIC PAIN IN THESE PATIENTS. SO NOW ON TO VACCINES. THAT HAVE BEEN DEVELOPED FOR THE VARICELLA ZOSTER VIRUS. YOU ARE PROBABLY ALL FAMILIAR BY NOW, I'M SURE MANY OF YOU IN THIS AUDIENCE MAY HAVE RECEIVED THE VARICELLA VACCINE, ALSO CALLED VARIVAX, APPROVED BY THE FDA IN 1995, ZOSTAVAX WAS APPROVED BY THE FDA IN 2006. THE VARICELLA VACCINE ALSO NOPE AS THE OKA VACCINE WAS DEVELOPED IN JAPAN AS A LIVE VIRUS, A LIVE AT10 WAITED VIRUS, AND THE ZOSTER VACCINE IS IDENTICAL TO THIS VIRUS, HOWEVER, IT HAS THE 14 FOLD HIGHER TITER THAN VARICELLA VACCINE. THAT'S BECAUSE PEOPLE WHO ARE RECEIVING IT ARE IMMUNE, THEY'VE HAD CHICKEN POX, SO IN ORDER TO BE EFFECTIVE, THE DESIGNERS OF THE VACCINE DETERMINE THAT IT NEED TO HAVE A HIGHER CONCENTRATION GIVEN THE PRESENCE OF THE IMMUNITY. IN 2008, THE CDC RECOMMENDED ROUTINE VACCINATION AMONG PEOPLE AGED GREATER THAN 60. THE SHINGLES PREVENTION STUDY WAS A HUGE STUDY, A RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL OF 38,546 ADULTS WHO WERE 60 YEARS OF AGE OR OLDER. SO IT'S A VERY LARGE MULTICENTER TRIAL. JUST AN EXAMPLE OF WHAT IT TAKES TO TEST THE VACCINE. THE HYPOTHESIS WAS THE LIVE ATTENUATED - OKA/MERCK VACCINE WOULD DECREASE THE INCIDENCE AND SEVERITY OF HERPES ZOSTER AND/OR POST HERPETIC NEURALGIA. INCLUSION CRITERIA FOR THE STUDY WAS THAT YOU HAD TO BE 60 YEARS OF AGE OR OLDER, AND YOU HAD TO HAVE A HISTORY OF VARICELLA, CHICKEN POX OR IF YOU CANNOT PROVIDE DOCUMENTATION OF THAT, YOU WOULD HAVE HAD TO LIVE IN THE UNITED STATES FOR 30 OR MORE YEARS, BECAUSE STUDYS HAVE SHOWN THE MAJORITY OF THOSE PATIENTS HAVE HAD CHICKEN POX. SO THESE PEOPLE WERE ALL -- HAD VCV -- EXCLUSION CRITERIA, YOU HAD A HISTORY OF SHINGLES, THAT YOU WERE IMMUNOCOMPROMISED, THEY DIDN'T WANT TO ADMINISTER IT TO ANYBODY WHO WAS IMMUNOCOMPROMISED SINCE IT WAS A LIVE ATTENUATED VACCINE, AND THEY ALSO EXCLUDED PEOPLE WHO HAD CONDITIONS WHERE THEY COULD ESTIMATE THAT THEIR LIFE EXPECTANCY WAS LESS THAN 5 YEARS. THE PRIMARY END POINT OF THE SHINGLES PREVENTION STUDY WAS THE BURDEN OF ILLNESS. AND THIS WAS A COMPOSITE OF THE SEVERITY OF THE ZOSTER AND THE DURATION OF PAIN CAUSED BY HERPES ZOSTER. THIS WAS FIRST ASSESSED -- THIS WAS ASSESSED FOR EACH INDIVIDUAL PARTICIPANT BUT THEN A COMPOSITE BURDEN OF ILLNESS WAS THE PRIMARY END POINT THAT WAS ANALYZED BY THE STATISTICIAN. THE SECONDARY END POINT WAS POST HERPETIC NEURALGIA, AND IT WAS DEFINED AS PAIN OR DISCOMFORT WITH A PAIN SCORE OF GREATER THAN 3 OUT OF 10 ON A SCALE OF 10, THAT PERSISTED OR APPEARED MORE THAN 90 DAYS AFTER THE ONSET OF THE HERPES ZOSTER RASH. THESE ALL END POINTS ARE VERY IMPORTANT IN A CLINICAL TRIAL AND IS ALL PLEA DETERMINED SO THAT THE RESULTS THAT ARE OBTAINED ARE VALID VALID. SO THE SHINGLE PREVENTION STUDY REVEALED THAT COMPARED TO PLACEBO, THE ZOSTER VACCINE REDUCED THE BURDEN OF ILLNESS BY ABOUT 60%, THIS WAS SIGNIFICANT. THE INCIDENTS OF POST HERPETIC NEURALGIA BY 66.5%, AND THE INCIDENCE OF HERPES ZOSTER BY 51%, WHICH ACTUALLY WAS A TEAR SH YEAR OBJECTIVE. THE PRIMARY OBJECTIVE WAS BURDEN OF ILLNESS, THE SECOND WAS INCIDENCE OF POST HERPETIC NEURALGIA. THE VACCINE WAS WELL TOLERATED AND HAD MILD INDUCTION SITE REACTION COMPARED TO PLACEBO. LOOKING AT THIS A LITTLE DIFFERENTLY, A PAPER THAT FOLLOWED THE VACCINE STUDY THAT WAS ORIGINALLY PUBLISHED IN THE NEW ENGLAND JOURNAL IN 2005, THE VACCINE REDUCED THE BURDEN OF ILLNESS, AS I SAID ON A PRIOR SLIDE, IN ALL SUBJECTS 61.1% EFFICACY WAS THE EFFICACY OF THE VACCINE. HOWEVER, IF YOU LOOK AT THE DIFFERENT GROUPS, AGE 60 TO 69, THIS EFFICACY WAS MAINTAINED, HOWEVER, IN PARTICIPANTS WHO WERE 70 YEARS OF AGE OR OLDER, THEY SAW A DECREASE OF EFFICACY OF 55.4%. SO THAT WAS THE PRIMARY END POINT. WHEN YOU LOOK AT THE INCIDENCE OF ZOSTER, THE VACCINE EFFICACY AND PREVENTING THE INCIDENCE OF ZOSTER ALSO WAS FOUND TO BE DECREASED IN THE 70 OR GREATER AGE GROUP. HOWEVER, THE VACCINE EFFICACY FOR POST HER P HERPETIC NEURALGIA REMAINED UNCHANGED COMPARE THE TO THE 60 TO 69 GROUP AND THE OVERALL -- LOOKING AT THE OVERALL SUBJECTS. SO THIS WAS AN IMPORTANT FINDING FINDING. DESPITE ITS EFFICACY OF INCIDENCE OF ZOSTER NOT BEING MAIMAINTAINED AND THE BURDEN ILLNESS NOT BEING MAINTAINED, GIVEN THAT THIS IS SUCH A POTENTIAL SIGNIFICANT COMPLICATION IN AN ELDERLY POPULATION WHICH CAUSES A LOT OF MORBIDITY, IT WAS VERY ENCOURAGING TO SEE THAT THIS VACCINE HELD UP IN THE OLDER AGED PATIENTS. IN LOOKING AT THE DETAILS OF THE PAIN IN PERSONS WITH ZOSTER, AND THOSE WHO RECEIVED THE VACCINE AND THOSE WHO RECEIVED THE PLACEBO, THE MEDIAN DURATION OF PAIN IN PERSONS WHO DEVELOPED ZOSTER WAS SHORTER IN THE VACCINE RECIPIENTS AT 21 DAYS THAN THOSE WHO RECEIVED PLACEBO AT 24 DAYS, AND THIS WAS SIGNIFICANT, THERE WAS A P VALUE OF .03. THE DEGREE OF PAIN WAS ALSO LESS IN THE VACCINE RECIPIENTS I THAN THE PLACEBO -- COMPARED TO THE PLACEBO RECIPIENTS. LOOKING AT TIME TO EVENT, SO TIMED TO THE INCIDENCE OF POST HERPETIC NEURALGIA OUT TO FOUR YEARS, THOSE WHO RECEIVED THE ZOSTER VACCINE, YOU COULD SEE THAT IT REMAINED EFFECTIVE OUT TO FOUR YEARS. THE CUMULATIVE INCIDENTS OF HERPES ZOSTER SHINGLES ALSO THE VACCINE EFFICACY WAS MAINTAINED OUT TO FOUR YEARS. SO AFTER THIS TRIAL WAS COMPLETED, THE INDICATIONS FOR THE ZOSTER VACCINES WERE THIS WAS INDICATED IN ALL PERSONS WHO ARE 60 YEARS OF AGE OR OLDER, BUT IT WAS CONTRAINDICATED IN PERSONS WITH HEMATOLOGIC MALIGNANCY, BUT IT COULD BE GIVEN IN PATIENTS IN REMISSION THAT HAVE NOT RECEIVED CHEMOTHERAPY OR RADIATION THERAPY FOR THREE OR MORE MONTHS, CONTRAINDICATED IN PATIENTS WITH AIDS OR HIV INFECTION, WITH VERY LOW T CELL COUNTS, ALSO CONTRAINDICATED -- BONE MARROW TRANSPLANTS OR OTHER CAUSES OF T CELL DEFICIENCY. AND THAT IS BECAUSE -- TO SEVERE DISEASE THAT DR. COHEN DESCRIBED DESCRIBED. PATIENTS WHO ARE ON HIGH DOSE IMMUNOSUPPRESSIVE THERAPY, DAILY PREDNISONE AT MORE THAN 20 MILLIGRAMS A DAY, ANTITUMOR NECROSIS FACTOR, THE RECOMMENDATION IS TO WAIT FOR ONE MONTH AFTER STOPPING THESE TREATMENTTREATMENTS AND TO VACCINATE. PEOPLE WHO ARE ALLERGIC TO VACCINE COMPONENTS, NEOMYCIN AND GELATIN, THE VACCINE WAS ALSO CONTRAINDICATED IN THESE PERSONS. SO IN SUMMARY, THE ZOSTER VACCINE MAINTAINS ITS EFFICACY REGARDLESS OF THE AGE OF SUBJECT SUBJECT, IN THE YOUNGER PATIENTS, 60 TO 69-YEAR-OLDS, IT IS MEDIATED MOSTLY BY PREVENTING ZOSTER, SO THESE YOUNGER FOLKS DON'T HAVE THE PROBLEM WITH POST HERPETIC NEURALGIA AND OTHER COMPLICATIONS, SO PRIMARILY THE EFFICACY OF THE VACCINE IS SEEN BY PRESENTING SHINGLES. HOWEVER, IN THE OLDER PARTICIPANTS, WHO ARE 70 YEARS OR MORE, AS YOU SAW, WE LOSE THE EFFICACY FOR PREVENTING ZOSTER, BUT WE MAINTAIN THE EFFICACY FOR PREVENTING POST HERPETIC NEURALGIA. THIS IS A SUPPLEMENTARY STUDY DONE BY USING THE PARTICIPANTS IN THE SHINGLES PREVENTION STUDY AND WHAT WE'RE SEEING HERE IS WE ARE SEEING VACCINE RECIPIENTS WHO I DID NOT DEVELOP SHINGLES BUT WERE VACCINATED AND PLACEBO RECIPIENTS WHO DIDN'T GET THE VACCINE BUT DEVELOPED ZOSTER. AND WHAT WE'RE COMPARING IN THESE TOP TWO PANELS IS THESE WERE TWO DIFFERENT T CELL ASSAYS THAT WERE CONDUCTED. YOU CAN SEE THAT AT ONE YEAR, TWO YEAR AND THREE YEAR, AFTER VACCINATION, THAT THE T CELL RESPONSES WERE SPECIFIC T CELL RESPONSES TO WHAT'S SIMILAR IN THE RESI RECIPIENTS WHO RECEIVED THE VACCINE AND THOSE WHO DEVELOP NATURAL INFECTION SHINGLES. THIS IS IMPORTANT, SPECIFIC T CELL RESPONSES ARE POR IMPORTANT FOR PREVENTING US FROM GETTING SHINGLES IN THE FIRST PLACE. SHOWING THAT THE VACCINE EFFECTIVELY ELICITED IMMUNE RESPONSES. SO THE QUESTION CAME UP WHAT ABOUT YOUNGER FOLKS, SHOULD YOUNGER FOLKS WHO ARE THE NEXT DECADE DOWN, 50 TO 59 YEARS, THE VACCINATED, AND THERE WAS A STUDY DONE WHICH WAS A RANDOMIZED TRIAL, WHICH EVALUATED THE SAFETY AND EFFICACY OF THE VACCINE IN MANY, MANY SUBJECTS, 22,439 SUBJECTS WHO WERE AGED 50 TO 59 YEARS. AND THEY WERE RANDOMIZED AND GIVEN A SINGLE DOSE OF THE ZOSTAVAX VACCINE FOR PLACEBO, MONITORED FOR OCCURRENCE OF SHINGLES FOR ABOUT 1.3 YEARS AFTER VACCINATION. THEY FOUND THE ZOSTER VACCINE WAS QUITE EFFICACIOUS IN THE 50 TO 59-YEAR-OLD GROUP, AT 69.8%, AT PREVENTING SHINGLES. AFTER THIS, THE FDA-APPROVED THE USE OF ZOSTAVAX VACCINE IN THE 50 TO 59 YEARS OLDS, HOWEVER, THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES IS NOT RECOMMENDING THIS AT THE CURRENT TIME, AND PROBABLY THE MAIN REASON FOR THIS IS THAT THEY THINK IF YOU GIVE THE VACCINE THIS EARLY TO PARTICIPANTS, THEN THEY MAY DEVELOP WANING IMMUNITY DOWN THE ROAD, I'LL SHOW YOU SOME EVIDENCE THAT WILL REVIEW THAT THAT'S HAPPENING, AND THEN THEY WON'T HAVE VACCINE -- THEY WON'T HAVE THE ADVANTAGE OF HAVING BEEN VACCINATED 10 YEARS DOWN THE ROAD AND THEN THEY'LL HAVE TO BE BOOSTED AGAIN. SO THEY WANTED TO SEE WHAT WAS THE LONG TERM PERSISTENCE OF THE ZOSTER VACCINE EFFICACY, SO THE SHINGLES PREVENTION STUDY EVALUATED EFFICACY UP TO FOUR YEARS AFTER THE PARTICIPANTS WERE GIVEN THE VACCINE. THIS ASSESSED VACCINE EFFICACY OF STUDY OF THESE PARTICIPANTS, ALMOST SO MUCH THOUSAND OF THEM, UP TO 11 YEARS POST VACCINATION. SO COMPARED TO THE SHINGLES PREVENTION STUDY, WHICH YOU SAW THE VACCINE EFFICACY WAS MAINTAINED UP TO FOUR YEARS, FOR YEARS SEVEN TO 11 POST VACCINATION, THE VACCINE EFFICACY DECREASED IN THESE PATIENTS FROM 61.1% AT YEAR FOUR, TO 37.3% AT YEAR 11. FOR THE BURDEN OF ILLNESS, HERPES ZOSTER BURDEN OF ILLNESS PRIMARY END POINT. ALSO THE VACCINE EFFICACY FOR THE INCIDENCE OF POST HERPETIC NEURALGIA DECREASED FROM 66.5 TO 35.4% AT YEAR 11. AND FOR THE INCIDENCE OF HERPES ZOSTER, IT DECREASED FROM 51.3 TO 21.1. IN SUM, THE VACCINE EFFICACY PERSISTS FOR BURDEN OF ILLNESS, HAVE PERSISTED INTO YEAR 10, WHEREAS THE VACCINE EFFICACY FOR THE INCIDENCE OF THE ZOSTER PERSISTED ONLY UNTIL YEAR EIGHT. SO INVESTIGATORS HAVE BEGUN TO STUDY WHETHER A BOOST BECAUSE OF THESE RESULTS, WHETHER A BOOSTER DOSE FOR THE SHINGLES VACCINE SHOULD BE ADMINISTERED TO OLDER ADULTS WHO ARE 10 YEARS OR MORE AFTER THEY WERE GIVEN THE FIRST DOSE OF VACCINE. IN THIS STUDY THAT WAS RECENTLY RECORDED, THE SECOND DOSE OF ZOSTER VACCINE WAS ADMINISTERED TO 200 PARTICIPANTS WHO WERE 70 YEARS OF AGE OR OLDER. AND THIS WAS COMPARED TO T CELL IMMUNE RESPONSE TO PARTICIPANTS WHO WERE VACCINATED FOR THE FIRST TIME, SO THERE WAS A GROUP THAT WAS 70 OR OLDER, THERE WAS A GROUPS THAT 50 TO 69. I THINK THERE WAS A GROUP THAT WAS 50 TO 59. THEY FOUND THAT FOR SUBJECTS WHO WERE GREATER OR EQUAL TO 70 YEARS OLD, THEIR VZV-SPECIFIC IMMUNE RESPONSES, WAS SIGNIFICANTLY HIGHER AT BASELINE AND AFTER VACCINATION IN THIS GROUP THAT WAS GIVEN THE BOOSTER DOSE. AND IT WAS ACTUALLY THE RESPONSES WERE ACTUALLY COMPARABLE TO PARTICIPANTS IN THE SIX TO 60 TO 69-YEAR-OLD AGE GROUP. SO THE BOOSTER DOSE IMPROVED CELLULAR IMMUNITY BUT THE EFFECT ON THE INCIDENCE OF ZOSTER WAS NOT EVALUATED, SO GIVEN THAT CURRENTLY WE DO NOT HAVE DATA ON THE VACCINE EFFICACY FOR CLINICAL END POINTS, IT CANNOT BE FDA-APPROVED OR RECOMMENDED AT THIS TIME. AND NEW TYPE IN ADDITION TO THE LIVE VACCINE, THERE'S AN ADJUVANT HERPES ZOSTER SUBUNIT VACCINE THAT'S BEING EVALUATED, AND THIS IS A VACCINE THAT CONSISTS OF A GLYCOPROTEIN E AND ADJUVANT, AND THE ADJUVANT IS NOT FDA-APPROVED SO IT'S NOT KNOWN AT THIS TIME WHAT THE LONG-TERM EFFECTS OF THIS ADJUVANT ARE. HOWEVER, INVESTIGATORS HAVE STUDIED THIS IN A PHASE 3 RANDOMIZED TRIAL WITH A PLACEBO. THEY GAVE TWO INTRAMUSCULAR DOSES OF VACCINE AND PLACEBO TWO MONTHS APART AND FOLLOWED THESE PARTICIPANTS FOR 3.2 YEARS. WHAT THEY FOUND WAS THAT SUBUNIT VACCINE HAD A VERY HIGH VACCINE EFFICACY AGAINST THE INCIDENCE OF HERPES ZOSTER OF 97.2% OVERALL. AND THIS VACCINE EFFICACY WAS MAINTAINED IN THE OLDER AGE GROUP, THE 70 OR MORE AGE GROUP, AND WAS SIMILAR TO THE PARTICIPANTS IN THEIR 50s AND THE PARTICIPANTS IN THEIR 60s. THE COLUMN THAT SHOWS VACCINE EFFICACY, THERE WAS A TOTAL VACCINATED COHORT, MOD FATED VACCINATED COHORT CONSISTED OF PEOPLE WHO ONLY GOT ONE RATHER THAN TWO DOSES OF THE VACCINE AND PARTICIPANTS WHO HAVE HAD SHINGLES WITHIN 30 DAYS, THOSE PEOPLE WERE EXCLUDED FROM THIS MODIFIED COHORT. BUT YOU CAN SEE THE VACCINE EFFICACY WAS 90%, OVER 90% IN EACH OF THE DIFFERENT COHORTS. SO IN SUMMARY, ANTIVIRAL AGENTS HAVE BEEN SHOWN TO REDUCE THE DURATION OF LESIONS AND THE SEVERITY OF DISEASE BUT NOT THE INCIDENCE OF POST HERPETIC NEURALGIA. WE DEFINITELY NEED NEW IMPROVED TREATMENT FOR POST HERPETIC NEURALGIA. OR PERHAPS VACCINES THAT MAY MORE EFFECTIVELY PREVENT POST HERPETIC NEURALGIA. HERPES ZOSTER VACCINE IS EFFECTIVE BUT SUBOPTIMAL, ONLY 15% OF PEOPLE 60 YEARS OR OLDER HAVE GO TE GOTTEN THE HERPES ZOSTER VACCINE. AND THE NULL SUBUNIT VACCINE WHICTHE NEW SUBUNIT VACCINEWHICH LOOKS VER Y PROMISING GIVEN THAT IT MAINTAINS EFFICACY IN THE OLDER AGE GROUP, MAY HAVE EFFICACY COMPARED WITH THE ZOSTER VACCINE AND MAY BE USED IN IMMUNOCOMPROMISED PATIENTS BECAUSE IT'S NOT A LIVE VACCINE. THOSE VACCINES ARE CONTRAINDICATED IN THIS GROUP. WE SEE PROMISING T CELL RESPONSES IN THE BOOSTER DOSES, BUT STILL THE EFFICACY AND TIMING NEEDS TO BE DETERMINED AND FURTHER STUDIED. THANK YOU. [APPLAUSE] THANK YOU VERY MUCH. WE HAVE SOME TIME, I HOPE THERE ARE SOME QUESTIONS. PLOAS SPEAK INTO THE MICROPHONE. >> SO THE QUESTION IS ABOUT VIRAL SHEDDING AND WHETHER OR NOT THAT'S TAKEN CARE OF BY THE ANTIVIRALS OR WHETHER THERE IS SHEDDING OUTSIDE THE FLUID IN THE BLISTERS. >> SO THERE IS VIRUS IN THE BLISTERS RS AND YES, THE ANTIVIRALS HAVE BEEN SHOWN TO -- VIRAL SHEDDING. >> APART FROM THE FLUID IN THE BLISTERS, THAT IS, IS IT CONTAGIOUS EVEN IF YOU DON'T CONTACT THE FLUID? >> SO THERE'S BEEN RARE INCIDENCE OF AIRBORNE TRANSMISSION OF THE VIRUS, AND IT'S RARE AND IT'S MORE COMMON BUT STILL NOT COMMON IN IMMUNOCOMPROMISED -- PATIENTS WHO PRESENT WITH DISSEMINATED INFECTION LESIONS EVERYWHERE, THEY HAVE TO BE ON ISOLATION CONTACT AS WELL AS AIRBORNE -- THERE HAS BEEN THREE QOWRTS -- HERPES ZOSTER RESULTING IN DISSEMINATED DISEASE FROM THESE PATIENTS TO OTHER SUSCEPTIBLE PATIENTS IN HOSPITALS. >> CHIC CHICKEN POX, THE PEOPLE CAN BE INFECTED BY A PERSON WITH CHICKEN POX EVEN BEFORE THE RASH OF CHICKEN POX OCCURS. SO YOU DON'T NECESSARILY HAVE TO HAVE A RASH PRESENT AT THE TIME FOR CHICKEN POX. >> I'M FROM NIDA. I'M JUST GOING TO REPORT A CASE OF UNUSUAL SIDE EFFECT OF THE VACCINE, AND -- YES, JUST VERY SHORT, I GOT THE VACCINATION AND THEN IN THE SECOND LAST YEAR, AND UNTIL NOW, THIS LOWER LEG GOES NUMB, PAIN AND OTHER PAINS, AND IT'S NOT BEING REPAIRED BY MEDICATIONS AND I DON'T KNOW WHAT'S COOKING IN MY RIGHT LEG. >> YOU CAN DISCUSS IT AFTERWARDS AFTERWARDS. WE CAN'T TALK ABOUT AN INDIVIDUAL CASE. I THINK IT'S A LITTLE COMPLICATED. DO ANY OF THE FELLOWS OR STUDENTS HAVE QUESTIONS? >> MY QUESTION PERTAINS MORE TO LIKE THE MULTIPLE RECURRENCES OF ZOSTER BEING MISTAKEN AND IT'S ACTUALLY THE HERPES SIMPLEX VIRUS, WHICH I WAS NOT FAMILIAR WITH BEFORE YOU MENTIONED IT. I DON'T REALLY HAVE A SPECIFIC QUESTION ABOUT THAT, JUST IF YOU COULD MAYBE PROVIDE MORE INFORMATION ABOUT THAT. I WAS UNFAMILIAR WITH HERPES SIMPLEX BEING ABLE TO APPEAR OUTSIDE OF -- >> SO SOME PEOPLE CAN GET HERPES SIMPLEX INFECTION OF THE SKIN, FOR INSTANCE, WRESTLERS, HERPES GLADATORIUM, WHERE WRESTLERS ON A WRIST ELING MATT WRESTLING MATT, AND IT CAN REACTIVATE ON THE SAME AREA OF THE SKIN. IT'S UNUSUAL, MOST OF US THINK HERPES SIMPLEX IS COLD SORES OR GENITAL HERPES, BUT IF THE VIRUS DOES PENETRATE THE SKIN, YOU HAVE TO BREAK THROUGH THE SKIN, IT CAN EASKT THE DORSAL ROOT GANGLIA AND CAN REACTIVATE. AGAIN, WHEN PEOPLE HAD FREQUENT RECURRENCES, THAT'S WHAT WE THINK ABOUT. IF YOU JUST HAD ONE EPISODE, IT'S MUCH MORE LIKELY TO BE SHINGLES. >> SO DO WE HAVE UP WITH DISEASE MORE AGGRESSIVE THAN THE OTHER, LIKE DIFFERENT TIENDZ OF VZD, GENETICALLY SPEAKING? >> HAVE ABOUT BEEN PROBABLY 50 ISOLETTES SEQUENCED BUT THERE'S ONLY A SINGLE ZER SEROTIE. YOU CAN SEE SEQUENCE DIFFERENCES BUT -- AND YOU CAN USE THAT FOR EPIDEMIOLOGIC STUDIES BUT IT'S REALLY ONLY ONE TYPE OF VZD, SO WE ONLY NEED ONE VACCINE. >> AND DO WE HAVE DIFFERENT GENETICALLY SPEAKING PEOPLE THAT ARE MORE PRONE TO HAVING A MORE AGGRESSIVE FORM OF SHINGLES THAN OTHERS AND PEOPLE THAT ARE MORE SUSCEPTIBLE TO HAVING ZOSTER AT AN EARLIER AGE? OR A MORE AGRIST I AGGRESSIVE FORM OF THE DISEASE? >> PEOPLE WHO HAVE CONGENITAL T CELL IMMUNODEFICIENCIES, KIDS WITH SKIDS, SE OR OTHER GENETIC ABNORMALITIES THAT IMPAIR T CELL FUNCTION ARE MORE LIKELY TO GET SEVERE CASES OF ZOSTER. PEOPLE WHO HAVE ABSENT ANTIBODIES, THEY DON'T NECESSARILY HAVE THAT. THERE ARE PEOPLE WITH SOMETHING CALLED JOB SYNDROME, MORE LIKELY TO GET RECURRENT EPISODES OF TRUE ZOSTER THAN OTHER PEOPLE, BUT THE COMMON DENOMINATOR IS INDIVIDUALS WITH DEFECTIVE T CELL IMMUNITY. >> THANK YOU. >> WHAT OTHER DISEASES ARE ASSOCIATED WITH THIS RE RECRUDESCENECE, A LONG PERIOD WHEN AFTER THE ACUTE DISEASE, PEOPLE FEEL FINE, SUDDENLY SOMETHING HAPPENS AND IT FLARES UP. WHAT ARE DISEASES ASSOCIATED WITH THAT? I CAN THINK OF HEPATITIS B AS ONE. MAYBE POLYOMA VIRUS. ARE THERE OTHERS? >> SO THERE ARE A NUMBER OF VIRUSES, PEOPLE GET INFECTED WITH THE HUMAN PAPILLOMA VIRUS, THERE'S A LATENCY PERIOD WHEN PEOPLE CAN GET CERVICAL CARCINOMA, REALLY ALL OF THE LATENT VIRUSES THAT ARE LATENT CAN -- SOME OF THEM REACTIVATE VERY QUICKLY AS YOU MENTIONED BUT OTHER ONES, HEPATITIS B, YOU'LL GET INFECTED WITH IT AND MAYBE 30, 40 YEARS LATER, YOU COULD DEVELOP HEPATITIS B ASSOCIATED LIVER CANCER, SAME THING WITH HEPATITIS C, HTLV1. MANY, MANY YEARS LATER, ONE CAN DEVELOP SPASTIC PARAPARALYSIS. SO THERE ARE A NUMBER OF VIRUSES THAT TAKE A LONG TIME BEFORE THEY REALLY RESULT IN DISEASE. >> SO MY QUESTION COMING FROM SOMEONE WHO HAD SHINGLES PROBABLY WAY TOO EARLY GOT IT YEAR AFTER I STARTED COLLEGE, IS PSYCHOLOGICAL STRESS HAS SORT OF BEEN SHOWN AS SOMETHING THAT CAN EITHER CAUSE IMMUNOSUPPRESSIVE EFFECT OR AT LEAST CHANGE THE WAY THAT THE IMMUNE SYSTEM WORKS, IS THAT SOMETHING THAT HAS BEEN SEEN AS A RISK FACTOR FOR GETTING A SHINGLES ATTACK, ONE, AND TWO, BEING SOMEONE WHO IS PROBABLY ONE OF THE LAST PEOPLE WHO HADN'T GOTTEN SHINGLES OR VARICELLA VACCINE BEFORE IT WAS MANDATED AND HAD GOTTEN CHICKEN POX THE STANDARD WAY, WHAT'S THE SHORTEST TIME BETWEEN INCIDENTS OF CHICKEN POX, LATE SEE, THEN FIRST ATTACK OF SHINGLES THAT'S HAPPENED? >> YOU HAVE CHICKEN POX WHEN YOU'RE A VERY SMALL BABY, LIKE AN INFANT, THEY HAVE A HIGHER CHANCE OF HAVING SHINGLES DURING THEIR CHILDHOOD, SO WE'VE EVALUATED PEOPLE LIKE THAT, I SAW A BOY 7 YEARS OLD, PRESENTED WITH A CLASSIC SIGN OF SHINGLES ON A TEST. WE HAVE STUDIES WHERE WE LOOK FOR UNDERLYING IMMUNODEFICIENCIES TO TRY TO DETERMINE IF THERE'S SOME PREDISPOSITION TO GETTING SHINGLES AND THE RISK FACTOR THAT HAS BEEN NOTED IN OTHER STUDIES IS THAT IF YOU HAVE CHICKEN POX WHEN YOU WERE A VERY YOUNG CHILD, IN INFANCY, THEN YOU HAVE A HIGHER CHANCE OF GETTING SHINGLES VERY YOUNG. I DON'T KNOW WHAT'S THE SHORT SHORTEST -- WHAT THE SHORTEST TIME IS BETWEEN CHICKEN POX AND SHINGLES. >> WE'VE SEEN IMMUNOCOMPROMISED PAISHTSZ WHO GET CHICKEN POX AND THEN WILL GET SHINGLES JUST A FEW YEARS LATER. IN TERMS OF STRESS, THE EVIDENCE FOR STRESS AS A CAUSE OF SHINGLES IS NOT GREAT, THERE'S ANECDOTES, MANY PEOPLE WILL SAY THEY GOT STRESS AND SHING SHIN GELS BUT MANY HAVE STRESS AND DON'T GET SHINGLES. SO I THINK PEOPLE WITH SEVERE STRESS, IF YOU HAVE SEVERE ENOUGH STRESS, WHETHER IT'S GOING TO DEPRESS YOUR IMMUNE SYSTEM AND CAUSE REACTIVATION, BUT THERE'S NOT A GREAT CORRELATION THERE. >> REPEAT THE QUESTION, PLEASE, BECAUSE THERE ARE PEOPLE WHO CAN'T HEAR. >> I THINK HE WANTS TO KNOW THE SHORTEST TIME PERIOD BETWEEN CHICKEN POX AND SHINGLES. I DON'T KNOW IF ANYBODY KNOWS THAT. >> I REALLY DON'T KNOW BUT AGAIN, IF YOU HAVE AN INFANT WHOSE MOTHER, FOR INSTANCE, GETS CHICKEN POX AT THE TIME OF DELIVERY AND THE BABY HAS NO IMMUNE RESPONSE, DOESN'T -- ANTIBODIES WON'T TRANSFER TO THE BABY, BABY CAN BE BORN WITH CHICKEN POX AND GET ZOSTER REALLY A FEW YEARS LATER. I DON'T KNOW THE EXACT -- THE WORLD'S RECORD, THOUGH. YOU'D HAVE TO LOOK IN THE GUINNESS BOOK. >> HI, JEFF. >> DR. BURR NEL IS A PEDIATRICIAN, HE SAYS HE KNOWS OF A CASE OF ZOSTER 3 1/2 MONTHS OF AGE IN AN INFANT. MOTHER WHO -- CHICKEN POX. THANK YOU. >> HI, GREAT TALK. COUPLE OF QUESTIONS REGARDING THE VACCINES MENTIONED. FIRST LIVE ATTENUATED VZV VACCINE, IS THAT THOUGHT TO ESTABLISH LATE SEE WHEN IT'S ADMINISTERED? SECOND QUESTION REGARDING THE SUBUNIT VACCINE THAT WAS IN THE PHASE 3 TRIAL THAT YOU JUST SHOWED, ARE PEOPLE EVALUATING THE T CELL RESPONSES TO THE SUBUNIT VACCINE FOR THE PEOPLE WHO ARE VACCINATED AND ARE THERE ANY SORT OF JUST GENERAL THOUGHTS ON HOW THE CORRELATIVE PROTECTION FROM ZOSTER MIGHT VARY WITH AGE? >> THE FIRST QUESTION WAS DOES THE SHINGLES VACCINE ESTABLISH LATE SEE, AND IT DOES, BUT NOT AS EFFECTIVELY AS WILD TYPE VIRUS BECAUSE IT'S ATTENUATED AND DOESN'T REACTIVATE AS OFTEN. THERE HAVE BEEN VERY RARE CASE OF VACCINE ASSOCIATED SHINGLE-LIKE RASHES AND ACTUALLY THE INITIAL -- THE SHINGLES PREVENTION STUDY, BUT SUBSEQUENTLY THERE HAVE BNL REPORTS IN THE OTHER TRIALS OF ZOSTER-LIKE RASHES AND CHICKEN POX-LIKE RASHES AND THEY WERE ALL THE WILD TYPE. THEN THE SECOND QUESTION WAS FOR THE -- >> THE TYPE OF IMMUNITY THAT SUBUNIT VACCINE, THE SU, SUBUNIT VACCINE, NOT THE LIVE ATTENUATED, WHAT TYPE OF IMMUNITY DOES THAT INDUCE? >> I DON'T REMEMBER. >> SO I THINK IT'S BEEN SHOWN TO INDUCE BOTH ANTIBODY RESPONSES AS WELL AS VAIR SE VARICELLA ZOSTER -- NOT CD8s. THESE PEOPLE HAVE BEEN PRIMED, YOU'RE GETTING A BOOST, BUT THEY'VE SHOWN CD4 RESPONSES AND ANTIBODY RESPONSES. THE PROTECTION FOR ZOSTER IS AGAIN T CELL RESPONSES, BE THEY CD4 OR CD8, NOT ANTIBODY RESPONSES. SO BOTH LIVE ATTENUATED, AS WELL AS THIS VACCINE, PARTICULARLY BECAUSE OF THE ADJUVANT U GET A CD4 RESPONSE. >> I'M JUST WONDERING ABOUT THE POST HERPETIC NEURALGIA. I THINK YOU MENTIONED THAT AGE HAS SOME EFFECT SO YOUNGER PEOPLE DON'T HAVE AS MUMP PAIN, IMMUNOCOMPROMISED PEOPLE THAT THEY MAY NOT HAVE AS MUCH PAIN, SO IS IT CLEAR WHAT'S REALLY CAUSING THAT PAIN AND WHY IS IT LESS WHEN YOU'RE YOUNGER, WHEN YOU HAVE A SORT OF IMMUNOCOMPROMISED INFICTION >> I AWMS THOUGHT I ALWAYS THOUGHT IT WAS RELATED TO THE DEGREE OF INFLAMMATION THAT MAY BE AFFECTING THE NERVE GROUP, I'VE SEEN PLENTY OF PATIENTS WHO'VE HAD SHINGLES MULTIPLE TIMES, TRANSPLANT PATIENTS, AND THEY DOESN'T REALLY COMPLAIN OF POST HERPETIC NEURALGIA IN MY EXPERIENCE. >> IT'S THOUGHT TO BE DUE TO DAMAGE TO THE NERVOUS SYSTEM. MANY THINK IF YOU'RE YOUNGER, YOU HAVE MORE SORT OF RESERVE IN TERMS OF YOUR NERVOUS SYSTEM AND IF YOU'RE OLDER, THE NEURONS ARE MORE LIKELY TO SORT OF TIP OVER TO HAVE REALLY SEVERE DAMAGE. THERE ARE DIFFERENCES AS ONE GETS OLD NER TERMS OF THE TRANSPORT PROPERTIES N TERMS OF THE AXE ON -- BUT AGAIN IT'S NOT ABSOLUTELY CLEAR. THERE'S SOME SCIENTISTS THAT THINK IT'S DUE TO PER SYSTEM VIRUS -- PERSISTENT VIRUS REPLICATION BUT I THINK THE MAJORITY IS IT'S NOT PERSISTENT -- IT'S DAMAGE AND AGAIN THE OLDER YOU ARE, THE MORE LIKELY YOUR ORGANS AND THE NERVOUS SYSTEM IS TO NOT BE ABLE TO REPAIR THAT DAMAGE SO QUICKLY. >> SO WHY DO YOU THINK IN IMMUNOCOMPROMISED PATIENTS THEY DON'T COMPLAIN OF POST HERPETIC NEURALGIA? >> IF YOU'RE YOUNGER AND IMMUNOCOMPROMISED, YOUR ORGANS AND TISSUES ARE STILL MORE RESILIENT AND IF THERE'S DAMAGE, IT'S NOT GOING TO BE AS SEVERE. >> ARE THERE MORE OF LOGIC OR OTHER VARIATIONS THAT -- TO THE VIRUS THAT RESULT IN THE VARIATION IN DISEASE PATHOLOGY IN VARICELLA ZOSTER AND -- I MEAN, OR IS THAT JUST COMPLETELY RELATED TO THE LOCATIONAL INFECTION OF -- >> SO AS FAR AS I KNOW, A STUDY THAT MY PREDECESSOR PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDICINE, HE TOOK CARE OF A PATIENT WHO HAD VARICELLA AND THEN FOUR OR FIVE YEARS LATER DEVELOPED ZOSTER. THEY HAD BOTH ISOLETTES, AND THEY JUST DID RESTRICTION ENZYME MAPPING AND SHOWED THAT ISOLETTES WERE IDENTICAL AS FAR AS THEY COULD TELL. SO AS FAR AS WE KNOW, THE VIRUS THAT CAUSES ZOSTER IS THE IDENTICAL VIRUS THAT CAUSES VARICELLA, AND AS FAR AS WE KNOW, THERE ARE NO DIFFERENCES IN TERMS OF THE SEQUENCE OR IN TERMS OF ANY OTHER PROPERTIES OF THE VIRUS. >> FOR MOST OF THE VACCINE INFORMATION, I KNOW YOU MENTIONED THAT SOME PEOPLE WERE EXCLUDED FROM THE STUDIES WHO HAD PRESENTED WITH SHINGLES BEFOREHAND. WOULD IT BE BENEFICIAL FOR PEOPLE TO GET THE VACCINE ONCE THEY'RE OF AGE THAT HAVE HAD SHINGLES BEFORE? SO IT'S STILL -- >> YES, SO WITH TIME ALSO THE IMMUNITY WILL WANE BUT IF SOMEBODY HAS MORE RECENT SHINGLES, IF YOU REMEMBER THE BAR GRAPH WHERE IT SHOWS UP TO THREE YEARS, THE IMMUNITY WAS SIMILAR TO VACCINE INDUCED T CELLS IMMUNITY. SO PERHAPS WAITING LIKE THREE YEARS AFTER SOMEBODY HAS AN EPISODE OF ZOSTER BECAUSE THEY'VE ESSENTIALLY VACCINATED THEMSELVES. HOPEFULLY THEY'LL GET 10 YEARS WORTH OF VACCINE INDUCED IMMUNITY ON TOP OF THAT. >> HAVE THEY TESTED VACCINES IN ANYONE YOUNGER THAN 50? THAT YOU KNOW OF? >> NOT TO MY KNOWLEDGE. >> WHILE WE'RE PASSING AGAINST -- WHAT IS THERE ABOUT THE DORSAL ROOT GANGLIA OF THE VAGAS, IT SAYS THE VIRUS GOES EVERYWHERE, IN SOME PEOPLE IT WINDS UP IN THE CRANIAL NERVES, BUT THE PREDOMINANT DISTRIBUTION IS IN THE DORSAL ROOT GANGLIA, WHAT'S SPECIAL ABOUT THAT? >> THE QUICK ANSWER IS WE REALLY DON'T KNOW, AND THERE ARE DIFFERENCES IN THE SENSORY NEURONS WE'RE TALKING ABOUT, THERE'S A TRANSDESCRIPTION FACTOR WHICH SEEMS TO BE IN THE CYTOPLASM OF THOSE PARTICULAR NEURONS AND IT'S DIFFERENT THAN IN OTHER TYPES OF NEURONS, AND THAT HCF 1 MOVES TO THE NUCLEUS WHETHER VIRUS REACTIVATES, WHEN HSV REACTIVATES IN THE SAME TYPE OF NEURONS. BUT THE SHORTER ANSWER IS WE REALLY DON'T KNOW AND PEOPLE ARE TAKING VARIOUS MONOCLONAL ANTIBODIES AND TRYING TO SEE WHAT'S SPECIAL ABOUT THOSE PARTICULAR NEURONS, WHY IT'S LATENT THERE. THAT'S SPHOR SOMETHING FOR THE FUTURE OR SOMETHING FOR THE YOUNGER PEOPLE IN THE AUDIENCE TO FIGURE OUT. >> THAT'S A VERY EXCITING AREA. I WAS READING RECENTLY THE EVIDENCE THAT PARKINSON'S DISEASE, THEY START OUT AS A DISEASE OF THE DORSAL ROOT GANGLIA OF THE VAGAS, ALPHA SYNUCLEIN ACCUMULATES THERE, AND THEN LIKE MAGIC MIGRATES FURTHER UP EFFICIENTLY TO THE BAIP SAL GANGLIA, SO THERE MUST BE -- >> SO A PATIENT COMES IN WITH SIMILAR SKIN SYMPTOMS AS ZOSTER. WHAT ARE OTHER CONDITIONS THAT MAY PRESENT SIMILAR SYMPTOMS? WHAT CAN PHYSICIANS CONFUSE ZOSTER WITH? >> AS WE MENTIONED, HERPES SIMPLEX ALSO CAN PRESENT VERY SIMILARLY. SO WE UNROOT THE VESICLE AND WE BASICALLY SCRAPE THE BOTTOM AND PUT IT IN MEDIA AND PERFORM TCR USUALLY TO DETECT THE DNA. ALSO A CONTACT DERMATITIS CAN POTENTIALLY PRESENT A. BUT WHAT'S CHARACTERISTIC IS THE DERMATOMAL DISTRIBUTION AND CLASSIC SHINGLES IS PRETTY CLASSIC, BUT ONCE WE SAW A PATIENT WHO HAD LESIONS HERE AND SHE WAS TOLD SHE HAD SHINGLES, WE UNROOT THE LEGIONS -- IT WAS INDEED HFC. SO IT'S PRETTY EASY THESE DAYS TO DISTINGUISH THOSE TWO VIRUS. >> MOST OF THE OTHER RASHES WILL CROSS THE MIDLINE UNLIKE CONTACT DERMATITIS, OR HSV, MOST OF THE OTHER ONES WOULD BE BILATERAL. >> OKAY. DO YOU HAVE A QUESTION? >> ONE LAST ONE. I WAS CURIOUS ABOUT THE TISSUE-SPECIFIC LOCALIZATION AND IF THAT'S THOUGHT TO BE A FACTOR OF VIRAL REPLICATION ALONE OR ALSO MAYBE LOCALIZED TISSUE IMMUNITY. >> SO I THINK AGAIN THE VIRUS IS IN THE BLOODSTREAM WHICH GETS INTO ALL THE VARIOUS TISSUES, AND WE'LL SEE PATIENTS, IF YOU MEASURE THEIR LIVER FUNCTION TESTS, THERE'S A LOW LEVEL OF APPLICATION OF THE VIRUS IN THE LIVER, SO I ACTUALLY THINK IT GETS INTO MOST OF THE TISSUES AND PROBABLY REPLICATED MORE OR LESS TO INDIVIDUAL TISSUES, BUT IT'S REALLY WHAT WE DETECT WHEN WE SEE PATIENTS OR WHAT PATIENT SYMPTOMS OR SIGNS OF BLOOD TEST TESTS, AND IN CELL CULTURE, IT REALLY AFFECTS A VAST -- LIVER CELLS, LUNG CELLS, VERY SPECIFIC FOR HUMAN CELLS. >> ARE YOU TALKING ABOUT SPECIFIC PREDELICKSES OF THE NERVOUS SYSTEMS? >> IN SHINGLES IS REACTIVATING, WHY DOESN'T IT CROSS INTO DIFFERENT DERMATOMES IF IT'S IN THE BLOOD, WHY IS IT THAT SYMPTOMS ARE SPECIFIC TO ONE PARTICULAR DER MA TOMORROW? >DERMATOME? >> IT REACTIVATES IN ONE OR TWO, LET'S SAY, DORSAL ROOT BEGAN IMLETBLEE A.THERE USUALLY IS A LOW LEVEL O F VIREMIA THAT OFTENTIMES YOU ONLY DEDETECTIVE BY NESTED DCR, SO JEBLY SPEAKING IT'S DUE TO THE NERVE WHERE IT'S REACTIVATING FROM. >> THANK YOU. >> IN ARE NO OTHER QUESTIONS, THANK YOU FOLKS VERY, VERY MUCH. 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