>> GOOD AFTERNOON AND WELCOME TO CLINICAL CENTER GRAND ROUNDS. MY NAME IS DR. RODNA, STAFF CLINICIAN IN THE DEPARTMENT OF RADIOLOGY IS IMAGING SCIENCES AND IT'S MY PLEASURE TO WELCOME TO YOU THE FIRST NEW CLINICAL PATHOLOGIC GRAND ROUNDS. TODAY'S CASE IS THE FIRST OF A NEW QUARTERLY GRAND ROUNDS SERIES MEANT TO ILLUSTRATE COMPLEX CLINICAL CASES CARED FOR HERE AT THE CLINICAL CENTER REINTEGRATED SERVICES CRUDING PRESENTATIONS OF PATIENT'S CLINICAL COURSE, RELEVANT LAB FINDING, ANATOMICAL IMAGING AS WELL AS DISCUSSION OF RESEARCH TO PATIENT MEDICAL CONDITION, IN DOING SO THE AIMS OF THESE CLINICAL PATH LOGIC GRAND ROUNDS ARE TO ILLUSTRATE COMPLEX MEDICAL CASES, THAT ADVANCE MEDICAL EDUCATION, BUT ALSO HIGHLIGHT THE PATIENT CARE, CLINICAL AND TRANSLATIONAL RESEARCH THAT IS ONGOING HERE AT THE CLINICAL CENTER. THE TITLE OF TODAY'S CLINICAL PATHOLOGIC GRAND ROUNDS IS: NOVEL, INSIDIOUS, PROGRESSIVE AND FATAL: THE DISCOVERY OF ASPERGILUS TANNERI. IT IS MY PLEASURE TO INTRODUCE OUR SPEAKER, DR. STEVEN HOLLAND, CHIEF LABORATORY CLINICAL INFECTIOUS DISEASES HERE AT THE NIH. DR. HOLLAND? >> THANK YOU VERY MUCH DOCTOR. SO IT REALLY IS A PLEASURE TO BE HAVING THE OPPORTUNITY TO START THIS NEW SERIES AND I WILL REITERATE THROUGHOUT AND WILL COME BACK AT THE END TO HOW YOU CAN CONTRIBUTE CASES TO THIS SERIES BECAUSE THIS IS WHAT MAKES US A CLINICAL CENTER, IT IS BRINGING TOGETHER THE CLINICAL, MOLECULAR AND CELLULAR ALONG WITH THE PATHOLOGIC TO REALLY UNDERSTAND OUR PATIENTS AND THEIR PROBLEMS BETTER. SO I'M GOING TO TELL YOU BRIEFLY A STORY AND I WILL REMIND YOU THAT HAVE NO DISCLOSURES AS IS TRUE FOR VIRTUALLY EVERYONE IN THE AUDIENCE. OUR OBJECTIVES ARE THE OBVIOUS ONES, WE'RE GOING TO TRY AND MAKE INTELLIGENT STATEMENTS ABOUT COMPLICATED THINGS AND THAT'S THE WAY IT GOES. SO OUR PATIENT, IT WAS A 19 YEAR-OLD CAUCASIAN MAN. AT TWO MONTHS OF AGE HE WAS DIAGNOSED WITH X-LINK CHRONIC GRANULA DISEASE AND IN ADDITION TO THAT HE HAD A DELETION OF A NEARBY GENE CALLED XK OR THE KELL, ANTIGEN THAT GAVE HIM THE Mc CLOUD PHENOTYPE WHICH I'LL MENTION LATER AND PART OF THIS DISEASE IS THAT HE'S UNABLE TO MAKE NUTRIFILL SUPEROXIDE WHICH IS INVOLVED IN KILLING MIKE ROBES, AT TWO QUEERS OF LIFE HE HAD A VARIETY OF PROBLEMS OF WHAT MIGHT HAVE BEEN TUBERCULOSIS AND FOR SPINAL ADNUMBER OF PATIENTSATHY, HE RECEIVED ANTITHERAPY. AT YEARS HE HAD AN UNUSUAL FUNGAL INFECTION, AND THAT CAUSED PNEUMONIA WHICH WAS TREATED AND RESOLVED. AT 13, HE HAD UREATERAL DILATATION AND REQUIRED A STINT PLACEMENT, THIS IS A CHARACTERISTIC PROBLEM IN THE X-LINK FORM OF CHRONIC GRANULA DISEASE AND HE ALSO HAD STAFF O COCKAL AND LIVER ABSCESS. NOW TO REMIND WHAT YOU THIS DISEASE IS AND HOW IT WORKS, YOU CAN SEE HERE THIS A KEEPATTIC OF A NUTRITILL AND THIS IS THE NUTRIFILL WITH GRANULES AND IN THE CYTOPLASM AND A FAB O RICE STUDIES OF MULTIPLE ENDOCRINE IN WHICH IT RECRUITS BACTERIA AND FUNGI. WHEN THAT COMES IN, THE GRANULES FUSE WIDE THE PH AGORICE STUDIES OF MULTIPLE ENDOCRINE AND THEY BRING IN THESE PROTEINS AND NUTRIFILL ELAST ACE AND THEY EMBED IN THE WALL FROM THE SECONDARY GRANULE, THESE PROTEINS KNOWN AS 91 AND 22. WHEN THOSE PEPTIDES ARE EMBEDDED, NOW HAVE YOU THIS COMPLEX TO WHICH CYTOPHRAZ MIC FACTORS JOIN AND SO NOW HAVE YOU THIS COMPLEX HERE EMBEDDED IN THE BALL OF THE PH AGOLIAISON STUDIES OF MULTIPLE ENDOCRINE, NADP H AND RIPS OFF THE ELECTRON FROM IT AND CONTRIBUTES IT TO MOLECULAR OXYGEN. SUPEROXIDE DISMUTASE CONVERTS THAT TO ACID AND IT CONVERTS IT TO BLEACH WHICH IS WHY WHITE CELLS ARE WHITE. THAT'S A HALLOWEEN JOKE. USE THAT AT THE DOOR. BE READY NOW. [LAUGHTER] ALTHOUGH IT WAS THOUGHT FOR MANY YEAR ITS WAS THE GENERATION OF BLEACH THAT KILLED THE BACTERIA AND THE FUNGI, WE NOW KNOW THAT THE MECHANISM IS REALLY MORE COMPLEX AND THAT WITH THE GENERATION OF A NEGATIVE CHARGE ON THE RICE STUDIES OF MULTIPLE ENDOCRINE, A CHANNEL OPENS AND AYE HIGH LEVELS OF POTASSIUM FLOW IN LEADING TO THE LIBERATION OF THESE PEPTIDES HERE THAT ACTUALLY GO AND DO THE KILLING OF BACTERIA AND FUNGI. SO IT'S A COMPLEX MECHANISM TO ACTIVATE A FLUX OF A--OF A MINERAL THAT LEADS THEM TO KILLING OF BACTERIA AND FUNGI THROUGH AN INDIRECT MECHANISM. NOW IN IS IMPORTANT BECAUSE MUTATIONS IN ANYONE OF THESE FIVE GENES THAT ASSEMBLE THE NADP H OXIDASE, MUTATIONS OF ANY OF THESE FIVE LEAD TO A VERY SIMILAR DISEASE KNOWN AS CHRONIC GRANULA DISEASE, IT COMES IN FIVE GENOTYPES BECAUSE THIS IS EXAMPLES OF CONVERGENT GENOTYPES ON A SINGLE PHENOTYPE AND THEN YOU CAN SEE THAT THE MOST COMMON CAUSE AND INDEED THE MOST SEVERE IS THAT CAUSED BY THE GENE THAT'S ON THE X-CHROMOSOME WHICH IS KNOWN AS CYBB, OR GP91 FOX. THE FREQUENCY IS SOMEWHERE BETWEEN ONE AND 101 AND 200,000. THE DIAGNOSIS IS USUALLY MADE IN CHILDHOOD BUT MORE AND MORE CASES ARE RECOGNIZED IN ADULTS AS WE DEVELOP LESS EXPOSURES IN THE ENVIRONMENT IN CHILDHOOD AND ALSO AS WE PROLIFERATE MUCH BETTER ANTIBIOTICS THAT ARE USED SOMEWHAT INDISCRIMINATELY. THERE ARE ONLY A FEW INFECTIONS THAT OCCUR IN CHRONIC GRANULA DISEASE AND THEY INCLUDE THESE STANDARDS, STAFF, SERERATEIA AND ASPERGILUS AND IF YOU ARE OUTSIDE NORTH AMERICA, SALMONELLA AND BCG ARE VERY COMMON. THERE ARE VERY FEW THAT ARE REALLY PATHOPNEUMONIC FOR CHRONIC GRANULA DISEASE, FILLA MORRAGIA AND GRANULAR DENSEUS, NONAPOPTOTIC THE MEDICAL STUDENTS IN THE AUDIENCE, IF YOU LEARN TO PRONOUNCE THESE, YOU CAN FOLLOW ROUNDS IN THEIR TRACKS. NO TAEBDING WILL BE ABLE TO FOLLOW UP ON THOSE QUESTIONS. SO THIS PATIENT TODAY, OUR PATIENT HAD THE X-LINK FORM OF GRANULA DISEASE DUE FOCUSED ON A DISCIPLINARY LESION HERE IN GP 91 AND THAT LED TO THE INABILITY TO CREATE SUPEROXIDE AND THE INABILITY TO RECRUIT THE MECHANISMS TO KILL INTRACELLULAR PROBLEMS. BUT HE DIDN'T JUST HAVE THAT, AND THAT'S CRITICAL IN UNDERSTANDING THE COMPLICATIONS IN HIS CASE. BECAUSE HERE THIS GENE CHRONIC GRANULA, CYBB, THIS WAS THE FIRST GENE THAT WAS MAPPED POSITIONALLY AND THEY DID IT BY RECOGNIZING SOMEBODY WHO HAD SEVERAL PROBLEMS ALTOGETHER, THIS GUY HAD CHRONIC GRANULA DISEASE, DID YOU CHAN'S AND--DUE SHENS AND IT TURNS OUT THAT RIGHT NEXT DOOR TO THE GENE IS THE KELL, ANTIGEN THAT IS CRITICAL FOR ALLOWING AND CREATING BLOOD GROUPS THAT ARE IMPORTANT FOR TRANSFUSION. THIS BOY HAD AN INTERSTITIAL DELETION IN THE X-CHROMOSOME THAT LED TO BOTH CGD AND THIS DEFICIENCY IN KELL, AND WHY IS THAT IMPORTANT? BECAUSE KELL DEFICIENCY LEADS TO THE Mc CLOUD SYNDROME AND THE Mc CLOUD SYNDROME LEADS TO A VARIETY OF RED CELL PROBLEMS AS YOU SEE HERE. THEY HAVE AN ELEVATED CPK, LATE IN LIFE THEY DEVELOP LIKE A HUNTINGTON LIKE DISEASE, NOW IN NORMAL PEOPLE WITHOUT CGD, THE ONSET OF THIS SYNDROME IS LIKE IN ADULTHOOD, THEY CAN HAVE CARDIO LOGIC AND NEUROLOGIC AND THEY'RE DIFFICULT TO TRANSFUSE BECAUSE THEY DEVELOP ANTIBODIES AGAINST THE KELL ANTIGEN ON THE TRANSFUSED RED CELL SO THEY CAN'T BE TRANSFUSED MORE THAN ONCE AND THEY'RE VERY DIFFICULT TO TRANSPLANT ONCE THEY BECOME ALLO IMMUNIZED. SO, IT'S HISTORY TO CONCLUDE HERE, AT AGE 17, HE HAD BEEN A VERY ACTIVE, VERY ENGAGED YOUNG MAN OUT IN LOS ANGELES, AT AGE 17, HE DEVELOPED NEWMONIA, WITH HOM OPTICAL IMAGES SIS, THAT TRANSIENTLY MADE HIM BETTER, A YEAR LATER HE DEVELOPED A NEW PNEUMONIA AND WITH WEIGHT LOSS AND FEVER, AT THAT POINT HE WAS PUT ON POSE CONSWROL BY AN ASTUTE INFECTIOUS DISEASE CLINICIAN IN CALIFORNIA AND A LUNG BIOPSY WAS OBTAINED AND THAT LUNG BIOPSY SHOWED ONLY INFLAMMATION, NO PATHOGEN WAS RECOVERED, DESPITE AN OPEN LUNG BIOPSY. AT THAT POINT, HIS PHYSICIAN CONTACTED US HERE AND SAID I DON'T KNOW WHAT HE'S GOT, IT'S GETTING WORSE COULD YOU PLEASE TAKE HIM TO THE NIH? HE WANTED TO KNOW WHAT IN THE WORLD IS CAUSING THIS? IS IT AN INDISCRIMINATE GRANULA PROCESS OR AN INFECTION? WHAT TO DO ABOUT IT? WHEN HE CAME HERE, IN DECEMBER OF 2010, KEN OLIVIA BRONCHED HIM AND SAW THE FOLLOWING ABNORMALITIES. YOU CAN SEE NODULES HERE ON THE VOCAL CORD AND HERE I HOPE YOU CAN MAKE OUT RIDGING AND ELEVATED STRUCTURES HERE IN HIS TRACHEA. AND THEN THIS IS IN DECEMBER, A MONTH LATER, THESE ARE MORE PROMULGATEINENT AND HE'S DEVELOPED A POP ILLEGALSOID LESION. CULTURES OF BOTH THE WHEREON COSCOPY AND THE SPUTUM GREW AN ASPERGILUS LIKE MOLD, LIKE BECAUSE THEY TRIED TO IDENTIFY IT MOLECULARLY AND IT WAS NOT ASPERGILUS AND IT WAS STERILE. NOW JUST THINK FOR A MINUTE, SOMEBODY CALLS YOU UP FROM THE MICRO LAB AND SAYS, YOU KNOW WHAT THIS IS A STERILE PROCESS THAT IS OVERRUNNING THE PLATE. AND YOU THINK HOW CAN IT BESTER AND I WILL GROWING HOW DO YOU GET THEM TOGETHER. BUT WHAT THEY'RE TRYING TO TELL YOU IS THAT IT'S NOT MATING, IT'S NOT DOING WHAT IT NEEDS TO DO FOR THE MOLECULAR. HE RECEIVED A VARIETY OF THERAPIES, NONE OF WHICH WERE SUCCESS. THINGS GOT WORSE, EXTENDED INTO THE LUNG INTO HIS PLURAL SPACE. SO ULTIMATELY, DESPITE EVERY EFFORT THAT WAS MADE HERE, HE DIED. WE WERE UNABLE TO GIVE HIM GRANUE LOW CITES BECAUSE OF HIS MISMATCH, HE WERE UNABLE TO DO A BONE TRANSPLANT BECAUSE WE COULDN'T FIND A DONOR WHO HAD KELL DEFICIENCY SO WE COULD GO IN WITH THAT AND THEN, TO YEARS AFTER THE ONSET OF HIS INITIAL DISEASE, HE TIED AND THEN DIED AT HOME, WE WERE VERY SUCCESSFUL IN GETTING HIM HOME FOR HIS LAST FEW DAYS AND THEN CAME BACK HERE FOR AN AUPS. SO I'M GOING TO STOP HERE, WE'LL COME BACK AND TALK ABOUT OTHER ASPECTS OF HIS CASE LATER. SO TO CONCLUDE, HE'S A 19 YEAR-OLD MAN WITH CGD, HE HAD LUNG DISEASE WITH THERAPY THAT EXTENDED OUTSIDE THE LUNG, WHICH IS QUITE UNUSUAL IN CGD, DO A MOLD THAT WE COULD NOT CHARACTERIZE AND WAS NOT ABLE TO REPRODUCE INVITRO. SO WHAT WAS IT? AND WHY WAS IT FATAL? SO I'LL NOW TURN IT OVER TO DR. VANKATUSSIN, WHO WILL NOW TALK ABOUT HIS IMAGING. >> THANK YOU DR. HOLLAND. IN REVIEWING THIS PATIENT'S IMAGING FINDINGS, IT'S ACTUALLY HELPFUL TO GO BACK AND LOOK AT HIS PREADMISSION SCAN, BOTH TO EVALUATE HIS BASELINE ABNORMALITYS BEFORE EVALUATEDDA THE NIH AND TO GET A SENSE OF THE CONISSITY OF THE PULMONARY DISEASE. HERE WE HAVE SELECTED IMAGES FROM THE PATIENT'S AUGUST 2010 CAT SCAN PERFORMED IN THE OUTSIDE HOSPITAL, WHEN THE SYMPTOMS THAT ULTIMATELY PROMPTED HIS ADMISSION TO THE NIH BEGAN. HERE WE CAN SEE EVIDENCE FOR RIGHT UPPER LOBE SUBSEQUENT TO SCARRING AND PREVENTIVE VOUS TO INFECTION, AND THIS IS WORSENED DISEASE COMPARED TO OLDER CAT SCANS AND POST OPERATIVE CHANGES FROM THE LUNG BIOPSY. WHEN WE FAST FORWARD TO THE IMAGING THE PATIENT HAD DONE AT THE NIH UPON INITIAL CLINICIAN, WE SEE THAT ALL OF THESE FINDINGS HAVE WORSENED SINCE AUGUST, THE PATIENT HAD EVIDENCE FOR A NEW RIGHT UPPER LOBE NODULE, WORSENING MIDDLE LOBE DISEASE AND YOU CAN SEE THE EVIDENCE AND YOU CAN SEE THE BRONCH I SURROUNDED BY THE INFECTED LUNG AND NEW RIGHT LOWER LOBE GROUND NODULES, THE DIFFERENTIAL FOR THESE FINDINGS WOULD INCLUDE EITHER A FUNGAL BACTERIAL OR FUNGAL PNEUMONIA. AT THAT TIME THE PATIENT HAD IMAGING OF HIS ABDOMEN WHICH WAS REMARKABLE FOR HEPATO SPHREPBD O MEGAL SCHECAN YOU SEE ON THIS REFORMATTED IMAGE, BOTH ENLARGEMENT OF THE LIVER AND THE SPLEEN. THIS WOULD BE SUSPICIOUS FOR UNDERLYING PORTAL HYPERTENSION AND SECONDARY TIME TO NODULAR REGENRATIVE HYPER PLASSIA OR DUE TO UNDERLYING INFILL ADMINISTRATIVE PROCESS, THOUGH PARTICULARLY WITH INFECTION WE EXPECT TO SEE FOCAL LESIONS THAT WERE EVIDENT AT THIS TIME. WE HAPPEN NONAPOPTOTIC 98 THE PATIENT WHO HAD A HISTORY OF REMOTE IVC OCCLUSION HAD A MARKEDLY NARROWEDICAL BURR IN FOR IBC IS DILATED VENUS COLLATERALS ENABLING THE STRAINAGE VIA THESE COLLATERALS WHICH DRAINED INTO THE AZYGUS AND HEMIAZYGUS IMAGING, THE THERAPY AS WAS DESCRIBED AND UNFORTUNATELY THE PROCESS OF THE MULTIFOCAL AND THE DISEASE. AND THE RIGHT UPPER LOBE IN THE DISEASE THAT WE CAN CONTRAST TO THE DECEMBER SCAN AT WHICH POINT A SOLTARY RIGHT UPPER LOBE NODULE PRESENT AND ALSO NOTED WAS INCREASING MIDDLE LOBE CONSOLIDATION WITH NEW LEFT LOWER LOBE GLASS NODULES AND AGAIN IN CONTRAST TO THE DECEMBER SCAN WE SEE GREATER OBLITERATION OF THE ARE--ADMINISTRATIVEERATED BRONCH I WITHIN THE MIDDLE LOBE WITH THE CONSOLIDATION AND IN THE RIGHT LOWER AIR SPACE DISEASE. WHICH WHEN COMPARED TO THE DECEMBER SCAN, WE KNOW MOST DEPRAOERBSABLY ALONG THE POSTERIOR DEPENDENT RIGHT PLEURAL SPACE. THESE COLLECTIVE FINDINGS ARE CONSISTENT WITH WORSENING OF THE MULTIFOCAL PNEUMONIA DESPITE THERAPY AND'S. ABDOMINAL MRI WAS PERFORM INDEED THE SYMPTOMS OF LEFT LOWER CHEST PAIN, ONE MONTH LATER GIVEN CLINICAL CONCERN IN THE SETTING OF HIS KNOWN SPINAL MEGALY AND THIS REVEALED HEPATO SPLENOMEGGALY AND A 2.5 CM FOCUS OF HYPOENHANCEMENT IN THE SUPERIOR ARSSPECT OF THE SPLEEN, MOST CONSISTENT WITH A SPLENIC INFARCT WE WILL HAVE DISCUSSION OF FROM OUR PATHOLOGIC COLLEAGUES AS WELL. IN MARCH 2011 AFTER CONTINUED THERAPY WITH ANTIMICROBIAL AGENTS WE UNDERWENT HR I OF THE CHEST WITH SHOWED WORSENING AIR SPACE, WORSENING AIR MIDDLE LOBE DISEASE, RATHER UNCHANGED COMPARED TO A MONTH PRIOR AND WORSENED OVER ALL AT THE NIH, AND INCREASING RIGHT AND LEFT LOWER LOBE AREA SPACE DISEASE. A BRAIN MRI WAS PERFORM INDEED APRIL OF 2011 IN THE SETTING OF CHANGES IN MENTAL STATUS AND I'D LIKE TO THANK MY COLLEAGUE DR. NICK P A TRONAS FOR THE REVIEW OF THESE FINDINGS. HERE WE HAVE ENHANCED IMAGES OF THE BRAIN WITH THE ATTENTION TO THE ORBIT WHICH WERE REMARKABLE FOR THE PROMULGATEINENT ENHANCEMENT AT THE NERVE HEAD SUSPICIOUS FOR PAP LO EDEMA AS SEEN IN THE SETTING OF INTERCRANIAL PRESSURE AND AS WELL AS ENHANCEMENT OF THE LEFT SUPERIOR OPHTHALMIC BRAIN WHICH IS FOCAL, OBLIGATIONS NORMALLY PROMULGATEINENT AND ASYMMETRIC COMPARED TO THE RIGHT. IT WOULD INCLUDE OPHTHALMIC VAIN THROMBOSIS OR CONGESTION. NOTABLY GIVEN THE POSSIBILITY OF HUNTING DON LIKE DISEASE PHENOMENON, THE BRAIN WAS ESALTUATED FOR ANY EVIDENCE FOR STPRUBGTUREAL ABNORMALITIES TO HUNTINGTON'S DISEASE PER SE AND THERE WAS NO EVIDENCE FOR ABNORMALITIES NOR TO THE CORTICALE BRING VOLUME OR VENTRICULAR ARCHITECTURE AND GIVEN HIS EVIDENCE FOR EXTENSIVE PULMONARY DISEASE, NO EVIDENCE FOR EMBOL I TO THE BRAIN. SO IN SUMMARY OVER THE COURSE OF THE PATIENT'S EVALUATION, THE SALIENT FINDINGS INCLUDED WORSENING OF MULTIFOCAL PNEUMONIA WITH BROAD SPECTRUM MIKE ROBIAL THERAPY AND--MICROBIAL THERAPY AND INFLAMMATTORY DISEASE PROCESS, FOCAL SPLENIC AND HYPER SENSITIVE SPLENIC INFARCT OVER THE INTERIM AND CNS FINDINGS WITH EDEMA AND THROMBOSIS OR CONGESTION, INTERCRANIAL PRESSURE BUT IN THE ABSENCE OF A STRUCTURAL MOUTH LESION OR ATOMIC CAUSE FOR THESE SYMPTOMS. THE PATIENT'S GROWTH AND HISTOPATHOLOGIC FINDINGS WILL BE PRESENTED BY MY COLLEAGUE FROM THE DEPARTMENT OF PATHOLOGY. >> WE HAVE THE SPECIMEN FROM THE PATHOLOGY FROM THE PROCEDURE PERFORMED BY DR. OLIVIA, THE FIRST WAS A SMALL BIOPSY FROM THE RIGHT LOWER LOBE OF THE LUNG, IT SHOWED BRONCHIAL EPITHELIAL, HOWEVER THERE WAS NO ORGANISM OBSERVED ON GMS STAIN WHICH IS A SILVER STAIN WE USE TO IDENTIFY FUNGAL ORGANISMS. WE ALSO RECEIVED BRONCHIAL AVELAR LAVAGE FROM THE MIDDLE LOBE OF THE LUNG AND THIS SHOWED MARKED ACUTE INFLAMMATION AS SEEN HERE WITH NUMEROUS NUTRIFILLS BUT NINE GMS STAIN WAS NEGATIVE AS WAS A FIGHT STAIN FOR ACID FAST FACILLI. SO THE PATIENT EXPIRED IN CALIFORNIA, ON APRIL 11th 2011 AND UNRESTRICTED AUTOPSY WAS PERFORM OFFICE OF DIVERSITY APRIL 20th 2011. THE MOST PRONOUNCED WAS IN THE LUNGS, THERE WERE MULTIPLE BILATERAL ADHESIONS. BILATERAL PLURAL OCALATIONS MEASURING 0.5 TO 0.2-CENTIMETERS, BILATERAL FUNGAL CAVITIES, AS SEEN HERE, SOME OF WHICH CONTAIN GREEN MATERIAL WHICH WAS SUBSEQUENTLY SHOWN TO BE FUNGI, AS WELL AS CONSOLIDATION WHICH WAS MORE PROMULGATEINENT IN THE RIGHT LUNG AND THE BASE OF THE LUNGS, AND COMBINED HROUPBG WEIGHT FOR THIS PATIENT WAS 1750-GRAMS AND WE WOULD EXPECT A PATIENT OF THIS SIZE TO HAVE A LUNG WEIGHT AROUND 1200-GRAMS, THIS IS AN H& E STAIN SLIDE SHOWING A LUNG ABSCESS FILL WIDE NUMEROUS NUTRIFILLS AND WE FOUND THIS THROUGHOUT ALL THE LOBES OF THE LIVER THAT WE SECTIONED. WE ACTUALLY ALSO SAW THEN ON H& E, THESE HYPEFUL BRANCHED ORGANISMS, WHICH WERE THE FUNGI AND THE BRANCHING IS AT 45 TO 60-DEGREE ANGLES AND THE FUNGI MEASURE THREE TO 4-MICRONS, IN GREATEST DIMENSION, AND THIS IS AGAIN, THE SILVER STAIN HIGHLIGHTING THESE FUNGAL ORGANISMS WHICH WERE FOUND BILATERALLY. AND AS DR. HOLLAND MENTIONED, THERE WAS EXTRA PULMONIC SPREAD OF THE FUNGI, SO THERE WAS THIS RIGHT PECKERRALIS MAJOR CHEST WALL ABSCESS WHICH WAS NOT CONTIGUOUS WITH THE PLURAL CAVITIES AND ON MICROCOPPIC SECTIONS WE SEE NUMEROUS NUTRIFILLS AND AGAIN ON THE GMS STAIN, THERE ARE THESE NUMEROUS BRANCHED ELEMENTS, OTHER FINDINGS AT AUTOPSY INCLUDED HEPATO MEGALYS OF THE PATIENT'S LIVER WEIGHED 2500,-28-GRAMS AND A NORMAL LIVER WOULD BE AROUND 1500-GRAMS AND HISTOLOGICALLY, WE SAW NUMEROUS PIGMENT AND MACROPHAGES AND THE SIGNUE SOEUDAL SPACES AS WELL AS IN THE CENTRAL VAIN AND WE FAVOR THESE ABUNDANT MACROPHAGES TO BE THE CAUSE OF THE PATIENTS HEPATO MEGALY AND WE OFTEN SEE THESE BIG MENTORSHIP SKILLED MACK WOPHAGES IN PATIENTS WITH CGD AS A RESULT OF THEIR DISEASE AND ANOTHER FINDINGS THAT IS--FINDING THAT IS OFFENSE SEEN IN PATIENT WHICH IS WE DID NOT OBSERVE IN THIS PARTICULAR PATIENT IS NODULE RESERVE HYPER PLACIA ON THE PARTICULAR STAIN OF THIS PATIENT'S LIVER WE DID SEE REGENERATION IN SOME CORE THICKENING BUT IT WASN'T SIGNIFICANT ENOUGH TO MEET THE THRESHOLD FOR NRH. WE ALSO ROUGH ATOM PERFORMED GMS STAIN ON THE LIVER AND THIS WAS NEGATIVE FOR FUNGAL ORGANISMS AND THE PATIENT ALSO HAD PORTAL HYPERTENSION DUE TO HEPATO MEGALY AND THE PATIENT'S SPLEEN WEIGHED 830-GRAMS IN A NORMAL SPLEEN, IN THIS PATIENT WOULD BE AROUND 100-GRAMS. AND THERE WAS THIS SPLENIC INFARCT THAT WAS MENTIONED IN RADIOLOGY THAT MEASURED 2.5-CENTIMETERS IN GREATEST DIMENSION AND HISTOLOGICALLY, WE SEE ONLY INFARCT TO TISSUE AND PIGMENT OR MACROPHAGES WHERE ON THE GMS STAIN THERE WAS NO FUNGAL ORGANISMS IDENTIFIED. SO WE TOOK CULTURES AT AUTOPSY FROM MICROBIOLOGY FROM LEFT AND RIGHT LUNG WHICH SHOWED GROWTH OF A NONSPORRULATING MOLD WHICH COULD NOT BE IDENTIFIED BY GENOMIC SEQUENCING WHICH IS MOST CLOSELY RELATED ASPERGILUS, AND AGAIN, LIKE WE OBSERVED ON THE GMS SECTIONS FROM THE LIVER AND SPLEEN, CULTURES TAKEN FROM THE LIVER AND SPLEEN WERE NEGATIVE FROM MICROORGANISMS. SO IN SUMMARY, WE HAVE IN AUTOPSY WE HAVE THE PATIENT WITH GRANUE LOAMUS DISEASE, WITH COMPLICATIONS INCLUDING BILATERAL PNEUMONIA WHICH IS MORE PROMULGATEINENTOT LOWER LOBES AND THE ON THE RIGHT SIDE AND THE BILATERAL PLURAL OCULATIONS, BILATERAL LUNG CAVITIES AND SOME CONTAINING FUNGUS, THE RIGHT PECKERRALIS MAJOR FUNGAL ABSCESS, HEPATO MEGALY AND PORTAL INFILTRATION BY PIGMENT AND MACROPHAGES AND NUMEROUS MACROPHAGES AND WE ALSO EXAMINE THE BRAIN AS PART OF THE AUTOPSY WITH THE SPECIAL WITH THE PATIENTS WITH THE Mc CLOUD PHENOTYPE BUT THERE'S NO SIGNIFICANT PATHOLOGIC CHANGES NOTED IN BIG MENTORSHIP SKILL AND MACROPHAGES AROUND SOME BETHELS AND I'LL TURN THINGS OVER TO DR. JUNE QUONG, TO DESCRIBE THE MEDICATION OF THE FUNGI. >> THANK YOU. >> YOU HAVE SEEN THIS HISTOLOGICAL PICTURE AND WHENEE SEE THIS, THERE'S NO QUESTION THAT IT'S AN INVASIVE MOLD INFECTION AND THEN WHEN IT COMES TO ETIOLOGY, ONE CAN SAY THE HYPER DIMENSIONS AND THE PATTERN OF HNE STAINING CHARACTERISTICS IS VERY CONSISTENT WITH THE ASPERGILUS SPECIES AND ONE CAN IMAGINE THAT ASPERGILUS SPECIES SHOULD HAVE THIS 45-DEGREE ANKLE V-SHAPED HYPER BRANCHING WHICH IS CONSIDERED AS A HALLMARK FOR ASPER DWELLUSS AND WE DON'T REALLY SEE MUCH OF THIS TYPICAL STRUCTURES IN CGD PATIENTS, IT'S MORE OF A NEWT ROW PENIC PATIENTS WE SEE THIS, BUT WHEN WE LOOK AT THE BRANCHING, IT'S MORE LIKE 65-70 OR CLOSE TO 90-DEGREE BRANCHING AND HYPOGROWTH IS RATHER STUNTED HAVING NOB LIKE STRUCTURE INSTEAD OF VERY SMOOTH AND POINTED TIP. SO AT THIS POINT, ONE WOULD SAY, IT'S CONSISTENT TO--CONSISTENT WITH ASPERGILUS SPECIES AND ONE WOULD IMAGINE THAT 99% OF TIME, THIS CULTURE MUST BE ONE OF THESE: PRIMARILY OF ASPERGILUS SOUPAGATEUS AND MAYBE IF IT'S NOT THIS, THEN THE SECOND MOST COMMON WOULD BE ASPERGILUS MAJOR HIS, NOW THE FUNGUS THAT HAS ALL THE CHARACTERISTIC PIGMENT IS BECAUSE OF THE SPORES WHICH ARE PRODUCED AND HAVING BEARING THIS VERY UNIQUE COLORS. SO, WHEN YOU DON'T HAVE THIS STRUCTURE, THEN WE CALL IT STERILE MOLD AND THEN THERE'S NO COLOR OF THE KINNIESIA. WHEN THE MICROBIOLOGIC SERVICE, DR. CULTURE IT IS LUNG BIOPSY SPECIMEN AND THE WASHING CULTURE OFFICE OF DIVERSITY THE ROUTINE MIKEOLOGICAL MEDIA THAT THE CLINICAL CENTER USES AND THEN THIS, FROM THESE TWO SOURCES PRODUCED IDENTICAL MOLD, BUT LOOKED LIKE THIS. NOW THIS IS ONE OF THE NUMBER OF THAT CAME FROM THE PATIENT. NOW, WHEN YOU HAVE THIS SO CALLED STERILE MOLD, PHENOTYPICALLY IT'S IMPOSSIBLE TO IDENTIFY, BUT WE CAN TAKE MOLECULAR APPROACH. NOW, MOST COMMONLY TAKEN MOLECULAR APPROACH IS TO PC R AMPLIFY THE ITS ONE AND TWO SEQUENCE FROM THE RIBOSOME DNA CLUSTER BECAUSE UNIVERSAL FUNGAL PRIMER, IS AVAILABLE AND YOU AMPLIFY THE SEQUENCE AND BLAST AGAINST THE DATABASE, WHEN WHEN THE SURFACE HAS DONE THAT, THE 94% ADENTITY WITH THE ASPERGILUS ROBUSTUS AND ONE CAN SAY THIS HEMOLOGY IS NOT HIGH ENOUGH TO BE--HOMOLOGY IS NOT LIE ENOUGH TO BE THIS CONSTANT. AT THIS STAGE, THEY SEND THE CULTURES TO US, THE MICROBIOLOGIST SECTION. SO WE DID EVERYTHING THAT WE KNOW HOW TO TO MAKE FUNGUS SPONTANEOUS ACTIVITY SPIROLATE AND INDEED WE DID AND AS YOU CAN SEE, NOT ONLY ASPERGILUS TYPICAL ASPERGILUS LIKE HEAD, BUT THE SPORE CHAINS ARE PRODUCED AND SINCE THE IGS SEQUENCE SAID IT IS CLOSER TO ASPERGILUS ROBUSTUS THAN ANYTHING ELSE, THAN FIRST THING WE WOULD DO IS WHAT DOES ROBUSTUS LOOK LIKE? , YOU CAN SEE, IT'S VERY FAR FROM EACH OTHER, MORPH LOGICALLY, NOT EVEN SIMILAR MORPHOLOGY IS JUST VERY DIFFERENT, AT THIS POINT, WE WOULD SAY MAYBE IT'S A NEW SPECIES YET TO BE DESCRIBED. SO WE USE THE THREE PROTEIN COATING GENES WHICH ARE IN THE ORGANISM AND THEY'RE VERY FILAATIVE INFORMATIVE GENES. WHEN WE [INDISCERNIBLE] IT AND PLUGGED INTO THE EXISTING FILE O GENIC TREE OF THE ASPERGILUS, CAN YOU SEE THIS IS WHERE THE AND MOST COMMON PATIENT'S ISOLATE BELONG TO SO CALLED SECTIONS ARE COMBATING AND INDEED IT WAS CLOSER TO ROBUSTNESS THAN ANYTHING ELSE. THIS GROUP IS PRODUCED TO TOXIN KNOWN AS OCRATOXIN WHICH IS NEFF ROUGH ATOM TOX AND I CAN MAYBE CARCINOGENIC AND MAYBE IMMUNO SUPPRESSIVE SO THE NEXT QUESTION WAS: DOES THIS PATIENT ISOLATE PRODUCE OR NEW SPECIES PRODUCE OCRATOXIC? SO WHEN WE TESTED USING THE REPRESENTATIVE OCRA TOXIN PRODUCER AND COMMERCIAL STANDARD OF OCRATOXIN AND THEN IT WAS ABSENT WHERE THE MOST WELL KNOWN OCRA TOXIN INDEED HAD THIS PEAKED SO WE DECIDED THIS FUNGUS DOES NOT PRODUCE THE OCRATOXIN AND WE ARE ASKING QUESTION: IS THERAPY FAILURE DUE TO THE INNATE RESISTANCE OF THE FUNGUS TOWARD AVAILABLE ANTIFUNGAL AGENT? AND THE RESULT WAS: INDEED IT WAS. THE ASPERGILUS WERE RELATED TO TWO, AND THEY WERE GROWN ON THE INHIBITION ZONE ON E-TEST AND PATIENT ISOLATES MAYBE A LITTLE SLOW GROWTH TOWARD THIS AREA, BUT NO INHIBITORY ZONE AND THEN THEY WOULD BE THE SAME. THIS WAS THE SAME STORY WITH THE POSTA CONIA SWROL, AS WELL AS THE [INDISCERNIBLE] AND WE CAN SEE WHY THE THERAPY WOULD FAIL. NOW IF WE WEREN'T TO STUDY THE PATHOGENESIS OF THIS NEW SPECIES, WE NEED ANIMAL MODEL. SO THE QUESTION IS, IS THERE A DISFUNGUS AND PATHOGENIC MODELS. WE USE CGD MODEL AS WELL AS CORTICO STEROID TREATED IMOCCUPY O SUPPRESSED MODEL AND IN THE IMMUNO SUPPRESSED MOUSE MODEL, THE NEW SPECIES AND THE FUMEIGATED, THE VERULOUS WAS ALMOST EQUAL. EMPLOY HOWEVER, IN CGD MICE, FUMEIGATEUS KILLED MUCH FASTER AND NEW SPECIES WAS VERY CHRONIC AND KILLED SLOWLY. WHEN WE LOOK AT THIS MICE, IT WAS TREATED WITH HYDROCORTISONE AND AS YOU CAN SEE HERE, FUME GATEUS BY DAY EIGHT AND NINE, ALL THE BRONCHIAL TREES WERE COMPLETELY CLOG WIDE THE FUNGAL GROSS WHERE IN THE MICE INFECT WIDE THE PATIENT ISOLATE HAS ALREADY LEFT THE BRONCHIAL TREE AND IT WAS MOSTLY IN THE PATHWAY GIVES RANK MA. PERANK WA. YOU CAN SEE THE GRANULA JUST PACKED THE WHOLE LUNG, AND MUCH MORE DENSE THAN IN THE PATIENT ISOLATE ALTHOUGH THERE ARE ENOUGH GRANULA FOCI AND THIS IS THREE DAYS LATER, EVEN. AT THE TIME OF DEATH, IT LONG LOOKED LIKE THIS. HISTOPATHOLOGY SHOWED HUGE LESIONS CONTAINING FUNGI AND THIS THE SPLENOMEGGALY WAS VERY PRONOUNCED COMPARE TO THE CONTROL, ABOUT FOUR TIMES BIGGER. WE DIDN'T SEE FUNGAL HIGHLY IN THE SPLEEN BUT IT WAS VERY CONSISTENT WITH THE PATIENT CASE. NOW, THERE IS ANOTHER VERY INEXPENSIVE AND LESS HEADACHE KIND OF ANIMAL MODEL BECAUSE WE DON'T NEED ANYMORE PROTOCOL FOR THIS. AND THAT IS GALLERIA, VEX MOTHULAR A USED FOR SCREENING--VEX MOTH LARVA E SCREENING AND THIS IS HOW WHAT IT LOOKED LIKE AND IT IS INJECTED AND THIS IS CONTROLLED AND BY THE TIME IT IS KILLED BY FUNGAL DISEASE IT LOOKS LIKE THIS. INTERESTINGLY PATIENT ISOLATES KILLED MUCH FASTER THAN ASPERGILUS FUMEIGATEUS. NOW THIS IS NOT JUST DAYS BUT HOURS, THIS IS VERY QUICKLY INFORMATION AND VERY INEXPENSIVE MODEL. WHEN WE MADE THE HISTOLOGY OF THE DEAD LARVA YOU CAN SEE THE LESIONS BY THE NEW FUNGUS WAS JUST THROUGHOUT AND THE MOSTLY TISSUES WERE ALL COMPLETELY GONE WHEREAS ASPERGILUS FUME GATE US WERE HERE AND THIS SHOWS HOW FRAGMENTS IS MUCH SMALLER THAN HUGE NETWORK OF THE NEW FUNGUS. NOW BY THIS TIME, THEY WERE NAMED ASPERGILUS CANARYS AND THE SEQUENCES OF FOUR GENES WERE NOW DEPOSIT THE IN GENERATED BANK. WHY DO WE HAVE TO DESCRIBE THE FUNGUS AND GIVE IT A NAME? FIRST, AND PREVENTION FROM THE TIME OF DIAGNOSIS AND RATHER THAN WASTING ALL THESE ANTIFUNGALS. SELECT OPTIMUM METHOD FOR CULTURING TO INVESTIGATE, AND ECOLOGY OF THE SPECIES, IDENTIFICATION OF RISK AND PREVENTION OF INFECTIONS. I DON'T KNOW HOW MANY OF OF CASES HAVE GONE UNDIAGNOSED AND THEN JUST SAID STERILE MOLD INFECTION IN THE ADAPTATIONS ORIGINAL IMMUNO PRESENTATIONS SO I THINK NAMING THE FUNGUS, CHARACTERIZING AND PUBLISHING IS VERY IMPORTANT. THANK YOU. >> THANK YOU, JUNE, SO NOW WE TOLD YOU ABOUT THE CASE, WE TOLD YOU ABOUT THE MOLECULAR STUFF, LET ME CARRY ON FOR A FEW MORE MINUTE PRESIDENCY AND THEN WE TRIED TO KEEP THIS SHORT SO WE HAVE TIME FOR DISCUSSION BECAUSE TRYING TO ENGAGE OUR COMMUNITY IN THESE CASES IS REALLY WHAT WE'RE HERE TO DO. SO AFTER THIS FIRST CASE WASS IDENTIFIED AND JUNE AND HER LABORATORY SAID, BOY THIS, IS REALLY A DIFFERENT MOLD WITH A DIFFERENT PHENOTYPE AND A DIFFERENT GENOTYPE, THEN WE STARTED TO CAST BACK OVER ONE OF THE VERY RARE THINGS, THAT THE CLINICAL CENTER HAS AND THAT IS A REPOSITORY OF ISOLATES THAT GOES BACK DECADES, NOT MONTHS, JUST A COUPLE OF YEARS, DECADES AND JUNE AND YVONNE SHAE WHO HAD BEEN IN THE MICRO LAB BEFORE HAD REMEMBERED A CASE FROM 1996 OF A BOY WHO HAD A SIMILAR REFRACTORY MOLD THAT HAD STARTED IN HIS LUNG, RIDDLED THROUGH THE BODY AND WAS FATAL BEFORE HE COULD GET TO BONE MARROW TRANSPLANTATION. AND INTERESTINGLY, ENOUGH, THE PATIENT THAT GAVE HIS NAME TO THIS MOLD ASPER GILL US TANNERI WAS FROM LOS ANGELES, THE OTHER BOY WHO HAD THIS WAS FROM HERE IN NEW MEXICO. SO TWO PATIENTS, THE ONLY TWO SO FAR IDENTIFIED WITH THIS MOLD FROM THE SOUTHWEST. BUT YOU CAN'T IDENTIFY THE SECOND CASE UNTIL YOU IDENTIFY THE FIRST. SO, WHAT DID WE ACCOMPLISH IN THIS CASE? WE DID NOT CURE THIS PATIENT, DESPAOEUD ENORMOUS EFFORT BY EVERY TEAM IN THE HOSPITAL, BUT WE DID CARE FOR HIM AND I THINK WE CARED FOR HIM VERY WELL, HE WAS IN THE HOSPITAL FROM EARLY DECEMBER TO EARLY APRIL A LONG HOSPITAL STAY DURING WHICH TIME HE GOT WORSE BUT HE UNDERSTOOD HIS DISEASE BETTER AND WE UNDERSTOOD HIS DISEASE BETTER AND WE DID AN OUTSTANDING JOB PROVIDING HIM THE CARE THAT WAS NEEDED. IN ADDITION WE'VE DONE OUR BEST TO TURN HIS TRAGEDY INTO SOMETHING THAT WE CAN WALK AWAY AND DO SOMETHING BETTER WITH. SO WE CAME TO UNDERSTAND HIS INFECTION AND WE IDENTIFIED A NEW PATHOGEN AND WE IDENTIFIED A SECOND DACE SO WE THIS IS NOT AN ISOLATED PHENOMENON TO HIM AND WE IDENTIFIED A NOVEL DICHOTOMY AND SO JUNE STUDIED THESE MODEL AND THE MOUSE MODEL OVER MANY YEARS AND AS I RECALL THIS IS THE FIRST CASE OF A DICHOTOMY IN THE MORTALITY BETWEEN THOSE TWO MODELS SO SOMETHING QUITE UNIQUE TO THIS MOLD. AND THEN WHAT IS THE LARGER CONTEXT IN WHICH WE WANT TO PLACE THIS YOUNG MAN'S CASE. SO, REFRACTORY FUNGAL INFECTIONS REMAIN A MAJOR CAUSE OF MORBIDITY AND MORTALITY IN CHRONIC GRANULA AND IN FACT IF YOU READ IT, IT'S THAT THIS IS INFAR AND AWAY THE MOST SEVERE AND LIFE THREATENING PROBLEM THAT CGP PATIENTS GET. IT'S A MORBIDITY IN BONE CANCER, MARROW AND ORGAN TRANSPLANTATION, SO WHAT WE FIND IS NOT ONLY RELEVANT TO PATIENTS WITH A RARE IMMUNO DEFICIENCY BUT IT MIGHT BE RELEVANT TO A MUCH BROADER DISEASE AND AS ONE EXAMPLE OF THAT, I WANT TO SHOW YOU A GAFF FROM A PATIENT IN 2003 THAT WAS REALLY THE FIRST MAJOR REPORT OF ORA CONO SOL, AND THE TAKE HOME MESSAGE IS THAT DESPITE HOW SUCCESSFUL THE TREATMENT WAS OR AMP TERSIN, 2/3RDS OF PEOPLE SURVIVING THEIR FUNGAL INFECTION OR 3-QUARTERS, DESPITE THAT, BETWEEN 1 QUARTER AND ONE-THIRD OF PATIENTS WITH FUNGAL INFECTIONS CONTINUED TO DIE, AND AS YOU SUE FROM JUNE'S DAT AASPERGILUS FUMA GOTUS IS OVERWHELMINGLY SUSEPTIBLE TO CONO SWROL AND AMP TERSIN AND SO BECAUSE WE DON'T KNOW HOW MANY OF THESE CASES MIGHT HAVE HAD A MOLD THAT WAS NOT IDENTIFIED AT A MODEL MOLECULAR LEVEL, WE CANNOT KNOW WHETHER THE REFRACTORINESS REPRESENTS FAILURE TO DIAGNOSE ACE MOLD THAT WOULD NOT RESPOND TO THESE AGENTS THAT THEY RECEIVED OR REFLECT SOMETHING DIFFERENT. IT'S ONLY WITH THAT MOLECULAR IDENTIFICATION THAT WE CAN GO FORWARD. >> SO WHY ARE WE HAVE HAVING THESE PATHOLOGIC CONFERENCES? IT'S REALLY TO COME TOGETHER AROUND A PATIENT AND A PATIENT PROBLEM SO WE CAN DISCUSS THE DISEASE AND THE OUTCOME GLOBALLY AND PUBLICLY AND WE WANT TO BE VERY STRAIGHT FORWARD ABOUT THE PROBLEMS AND THE SUCCESSES. WE WANT TO SHARE WHAT WE'RE DOING, THE SUCCESSS AND THE IT'S CRITICAL TO MAKE SURE WE ARE GETTING INPUT ON THE COLLEAGUES, I'M CONSTANTLY AMAZED AS I GO AROUND THE NIH HOW MANY PEOPLE ARE DOING EXTRAORDINARY THINGS THAT ARE HIGHLY RELEVANT TO THE AREAS I'M INTERESTED IN, THAT I DON'T KNOW ABOUT BECAUSE I'VE NOT HEARD IT, THIS IS ONE PLACE WHERE WE USE THE WEDGE THAT WE MAKE SURE WE SHARE WHAT WE'VE GOT. I WANT TO JUST ACKNOWLEDGE IN CLOSING THE GROUPS INVOLVED. YOU KNOW THEY SAY, TO TAKE CARE OF A PATIENT IT REQUIRES A CLINICAL CENTER. HERE'S AN EXAMPLE. HERE THE PATIENT CAME INTO THE FIVE SOUTHEAST PATIENT TREATMENT AND TRINA AND EDWARD DID EXTRAORDINARY WORK TAKING CARE OF HIM. HE WAS CARED FOR BY THE LABORATORY OF CLINICAL INFECTIOUS DISEASES AND KEN AND OLIVIA WERE HEROIC IN THEIR CARE AND THEN THE NUMEROUS GROUPS THAT WERE INVOLVED, THE CLINICAL CENTER MIKE ON ROW BIOLOGY--MICROBIOLOGY LAB, AND CHRISTINA AND YVONNE, AND L LES, AND RODNEY, AND PATHOLOGY, AND GREG AND DAVE, AND THEN AND ONCE WE IDENTIFY WE DIDN'T KNOW THE ANSWER, TAKE IT TO THE INVESTIGATORRIVE LEVEL TO GET TO THE M LECULAR BIOLOGY WITH KHREPB AND THE LABORATORY POST DEFENSES WITH ELIZABETH KYANG WERE INTIMATELY INVOLVED WITH THE START FROM THE QUESTION OF COULD ME MAKE IT TO TRANSPLANT AND TRAGICALLY WE COULD NOT. AND THEN MANY OTHERS HAD TERRIFIC SUGGESTIONS ABOUT HOW TO TREAT HIS MOLD AND THEN MAKING THE FINAL IDENTIFICATIONS, THE LAB ROTORY OF THE USDA AND THE SEQUENCING GROUP AT THE RESEARCH TECHNOLOGY BRANCH WITH GLEN NARDONE, THIS REALLY REFLECTS HOW COMPLEX AND HOW BROAD A CLOTH WE HAVE TO SPREAD IN ORDER TO CATCH ALL THE THINGS WE THINK ARE CRITICAL TO UNDERSTANDING THIS DISEASE. FINALLY LET ME JUST ACKNOWLEDGE THE PATIENT AND THIS IS TANNER, WHOSE NAME WAS GIVEN TO THIS ISOLATE, HIS FAMILY WAS I THINK PROUD THAT EVEN IN HIS MOST TRAGIC TIMES HE WAS ABLE TO CONTINUE TO CONTRIBUTE ALSO ULS NOTICE TANNIC WAS AND THE KING VS A WEB SITE AND TANNER HAS A WEB SITE TO AND AND THEY SPEND TOGETHER AND I THINK TANNER MADE A TREMENDOUS IMPACT ON ALL OF THIS. FINALLY THIS IS A CHANCE TO TALK ABOUT PATIENTS AND PATIENT PROBLEMS. SPECIAL WE ARE HOPEFUL THAT PEOPLE WILL TAKE UP THE OPPORTUNITY TO PRESENT THEIR CASES AND IF YOU'VE GOT CASES YOU'D LIKE TO BE CONSIDERED, PLEASE SEND A BRIEF DESCRIPTION TO AROD NAAT THIS ADDRESS HERE AT THE CLINICAL CENTER AND HE IS LEADING THE EFFORT TO PUT THESE GRAND ROUNDS TOGETHER AND TO BRING THEM TO A COMMITTEE TO REVIEW AND TO SELECT THE CASES. ALL RIGHT, SO WITH THAT WE'LL CONCLUDE OUR FORMAL PRESENTATION AND ALL OF US WOULD LOVE TO BE GIVEN THE OPPORTUNITY TO ANSWER QUESTIONS ABOUT THIS CASE OR ONES LIKE IT, THANK YOU. [ APPLAUSE ] D. KD--SALLY CAN QUESTIONS FROM THE AUDIENCE ANY QUESTIONS FROM THE AUDIENCE. >> SO THE QUESTION IS DO WE HAVE ANY INSIGHT INTO THE MECHANISM? WOULD YOU USE THE MICROPHONE PLEASE BECAUSE WE'RE BEING BROADCAST. COME TO THE MIC IF YOU CAN TO POSE YOUR QUESTIONS. >> AT THIS POINT WE HAVE NO IDEA WHY THESE STRAINS ARE SO RESISTANT TO ANTIFUNGALS, SO FIRST THING TO DO IS THAT WE ARE GOING THROUGH THE GENOMIC SEQUENCING AND TO SEE IF THERE'S SO MUCH OF EFFLUX PUMPING OR WHETHER THE DRUG GETS IN OR WHETHER THERE ARE BIOSYNTHETIC PATHWAYS HAVE SOME UNUSUAL DELETIONS OR ANY OTHER MUTATIONS SO THAT IT'S NOT RESISTENT SENSITIVE TOWARD THE DRUG. WE DON'T KNOW YET. >> THANK YOU VERY MUCH FOR THIS PRESENTATION, THE QUESTION RELATES TO THE BONE MARROW TRANSPLANT, WE'RE HOPING TO BRING THIS PATIENT TO A SITUATION WHERE HE COULD BE A RECIPIENT OF A BONE MARROW TRANSPLANT BUT COULD YOU HELP US UNDERSTAND THE INDICATION AND APPROPRIATE TIMING, IT'S A COMPLEX QUESTION, SO,--AND I THINK THE QUESTION ABOUT WHAT'S THE APPROPRIATE TIMING IN CHRONIC GRANULA DISEASE IS DIFFERENT FROM THE QUESTION OF WHAT'S THE APPROPRIATE TIMING HERE? AND I THINK THE WORK OF HARRY MALIC'S GROUP HAS BEEN DRAMATIC AS WELL AS GROUPS IN EUROPE THAT CAN YOU SUCCESSFULLY DO A BONE MARROW TRANSPLANT IN THE SETTING OF ACTIVE INFECTION AND CHRONIC GRANULA DISEASE. THE RISKS OF CHRONIC GRAFT VERSES HOST DISEASE ARE HIGHER BUT SURPRISINGLY, REALLY QUITE SURPRISINGLY, THE MORTALITY IN THOSE PATIENTS TRANSPLANTED FOR PROGRESSIVE FUNGAL DISEASE HAS NOT USUALLY BEEN FROM THE FUNGAL DISEASE. AND THE EXPERIENCE HERE HAS BEEN HAS BEEN THAT THEY'RE ABLE TO GET THOSE THROUGH TRANSSKPHRAPBT SOME HAVE DIED, IT IS NOT BECAUSE OF PROGRESSIVE FUNGAL INFECTIONS, SO THE PROBLEM IN THIS BOY, WAS THAT BY THE TIME WE WERE READY TO GO TO TRANSPLANT, NOT ONLY DID HE NOT HAVE A GOOD MATCH, HE ALSO--WE WERE VERY CONCERNED THAT WE MIGHT NOT BE ABLE TO SUPPORT HIM FROM A BLOOD PRODUCT STANDPOINT, HIS PLATELETS WERE RATHER LOW, SO WE WERE QUITE CONCERNED THAT ME MIGHT NOT BE ABLE TO BE TRANSFUSED THROUGH THE PERIOD OF TRANSPLANTATION THAT WOULD BE REQUIRED. SO FOR SOME OF THESE PATIENTS AND THEIR HAVE BEEN TRANSPLANTS IN THE CLOUD PATIENTS BEFORE, FOR THOSE CASES, PEOPLE HAVE HAD TO EITHER BANK THEIR OWN BLOOD BEFORE HAND OR FIND A DONOR FROM AROUND THE COUNTRY AND Mc CLOUD IS QUITE RARE. A DONOR WHO WAS WILLING TO GIVE UP THE BANK UNIT IN ORDER TO DO THIS. SO I THINK WOULD WE DO THINGS DIFFERENTLY IN RETROSPECT, WE MIGHT. BUT BY THE TAME WE WERE READY TO CONSIDER TRANSPLANTATION, THE OPPORTUNITIES REALLY WERE NOT THERE. FINDING A MATCH FOR THIS YOUNG MAN WAS PARTICULARLY DIFFICULT. AND I THINK WOULD HAVE CONTINUED TO POSE A REAL OBSTACLE. >> SO SOME ASPERGILUS SPECIES WERE ACTED BY CO AG LOPATHYS? DID YOU HAVE A AN'RE ISSUE WITH THIS? >> SO THE QUESTION IS DID HE HAVE A CO AGULATION PROBLEM? I BELIEVE HE DID HAVE THAT, I DON'T REMEMBER A MORE SPECIFIC CO AGULATION ABNORMALITY AND I'M NOT SURE WHICH ONE YOU'RE REFERRING TO. >> WE DIDN'T NOTICE ANY SPECIFIC THROMBOSIS OTHER THAN THE INFARCT TO THE SPLEEN. >> I WOULD MAKE ONE COMMENT ON THAT, THOUGH, MANY PEOPLE SAY, WHY SHOULD I GET AN AUTOPSY. I KNOW EVERYTHING ALREADY, I'VE GOT THE RADIOLOGY, I'VE GOT EVERYTHING I NEED, WHY WOULD I PUT HIM THROUGH THIS. >> WELL, I WANT TO BE CLEAR WITH YOU, I WOULD HAVE SWORN THAT THIS MAN HAD PENETRATION OF ASPERGILUS THROUGH HIS DIAPHRAGM INTO HIS SPLEEN, I WAS A HUNDRED% CONVINCE THAD THAT'S WHY HE HAD A SPLENIC INFARCT AND I WAS COMPLETELY WRONG. AND WHEN WE SAW, HE BECAME--HE HAD A VARIETY OF ABNORMALTIES WITH THE DRUGS IN THE ABNORMALITIES IN THE ORBITAL BRAIN AND IN THE BRAIN, WE WOULD VALID SWORN THAT HE MUST HAVE METASTATIC DISEASE WITH THE ASPERGILUS TO THE EYE AND THE BRAIN, BOTH OF WHICH WERE INCORRECT. SO I THINK PART OF THE REASON WE NEED TO PUSH FORWARD AND DO OUR DAMN TEST TO MAKE SURE THAT PATIENTS HAVE AUTOPSYS, IT'S THE ONLY WAY WE FIGURE OUT WHAT WE KNOW AND WHETHER WE KNOW WHAT WE THINK WE KNOW. SO I HAVE TO TELL YOU, I WAS REALLY WRONG HERE ABOUT THINGS THAT I THOUGHT WERE GOING ON WITH HIM. AND IT WAS ONLY WITH THE PATHOLOGIST AND GOING BACK AND SAYING, ARE YOU SURE? ARE YOU SURE? WELL, THEY WERE SURE? I WAS WRONG. BUT THAT'S A CRITICAL THING TO LEARN. I DON'T KNOW ABOUT A CO AGUE LOPATHY OTHER THAN THE ONE YOU MENTIONED. >> IN TERMS OF THE FUNGI AND THE OTHERS, DO YOU KNOW WHAT WAS CHANGING THE CHANGES? >> JUST TO GET BACK TO THE QUESTION OF THROMBOSIS, I WILL MENTION THE PATIENT HAD A REMOTE HISTORY OF INPRACTICE HEPATIC IBC OCCLUSION WHICH WE DIDN'T HAVE A GREAT AMOUNT OF DETAIL ABOUT BUT I UNDERSTANDING WAS THAT IT OCCURRED AS A PEDIATRIC PATIENT AND AS I DEMONSTRATED WITH THE PATIENT'S IMAGING, WE DID SEE EVIDENCE FOR DILATED SUBCUTANEOUS VENUS COLLATERAL ENABLING VENUS TRAINAGE BY THE ADVOCATES SO THERE HAD BEEN A REMOTE HISTORY OF CABLE OCCLUSION WE DID NOT HAVE LABORATORY EVIDENCE THAT HE HAD A CO AGUE LOPATHY APART FROM THE LUPUS ANTICO AGUE RANT. >> SO I THINK THE QUESTION ABOUT WHAT CAUSES HEPATIC AND SPLENIC ENLARGEMENT. SO WE ACTUALLY HAVE THE WORLD'S EXPERT HERE IN THE ROOM, DR. HILLER WOULD YOU LIKE TO COMMENT ON WHAT--I'M NOT EVEN JOKING. YOU KNOW THIS--REALLY IS THE WORLD'S EXPERT ON THE LIVER AND SPLEEN AND CHRONIC GRANULA DISEASE. WOULD YOU CARE TO USE THE MICROPHONE? >> HE'S PUTTING ME ON THE SPOT. I'M A EXPERT BECAUSE I'VE SEEN TWO PATIENTS. NOT MUCH MORE THAN THAT. IT SEEMED LIKE HE HAD RETINOPATHYATHY AND CAN YOU--THAT MEANS DAMAGE TO THE VESSELS INSIDE THE LIVER. CAN YOU GET TENSION FROM THAT ALONE, YOU DON'T HAVE TO HAVE TYPIER TENSION TO DEVELOP THAT, BUT THAT ALONE IS ENOUGH. THAT WOULD EXPLAIN THE BIG SPLEEN AND I THINK THE PIGMENTED MACROPHAGES WAS MORE THAN AN ADEQUATE EXPLANATION AND IT LOOKED LIKE THE LIVER WAS KHOBGED FACULTY AND THE SINUSES WERE CHALKED FULL. AND IF YOU HAVE THAT MUCH IN THE SINUSOIDS, THAT CAN GIVE YOU HYPERTENSION. LEUKEMIA, OR LUNG CANCER MELANOMA INFILTRATING THE SINUS, YOU CAN GET TREMENDOUS BORDER LINE HYPERTENSION. THE. >> SO THE FLIP SIDE TO THAT IS THAT WHEN DR. QUANG SHAN, SHOWED YOU WHEN THE MICE ARE INFECTED, WHEN THE MICE ARE INFECTED THEY HAVE TREMENDOUS INCREASE IN SPLENIC SIZE AND I'M TRYING TO SORT THIS OUT. SO YOU KNOW WE KNOW THERE ARE THESE PIGMENTED MACROPHAGES, WE DON'T KNOW WHAT IT IS, WE DON'T KNOW WHY THEY DEVELOP THESE INTRANSLATIONAL RESEARCH CELLULAR COLLISIONS OF METHODS BUT WE TRY TO FIGURE OUT WHAT DRIVES THOSE AND WHAT'S THERE IS QUITE INTERESTING AND SO IT'S WORKING WITH CHRONIC GRANULA DISEASE MICE TO TRY AND SORT OUT EXACTLY WHAT HAPPEN WHEN IS THEY GET SICK AND HOW DOES THAT DRIVE SOME OF THESE CHANGES IN THE MORE EXPANSIVE GASTROINTESTINAL TRACT, IN THE HUMANS WE KNOW THAT THEY DEVELOP THESE PROBLEMS IN THE LIVER AND WE THINK THOSE DRIVE A LOT OF WHAT HAPPENS IN THE SPLEEN. >> SILLY QUESTION: DO HAVE YOU ENOUGH ORGANISMS STORED ALIVE THAT YOU COULD DO ANIMAL STUDIES BY AFFECTING A VARIETY OF SPECIES A VARIETY OF ANIMALS AND SEE WHAT HAPPENS TO THEM. >> YOU BET YOUR BIPPY! [LAUGHTER] DO WE HAVE ENOUGH ORGANISMS STORE THAD WE COULD DO A VARIETY OF INFECTIONS? >> YES, NOT ONLY STORED HERE BUT WE DEPOSITED AT NRRL, AND THEN ATCC, SO YOU CAN OBTAIN FROM THOSE PLACES, OR FROM OUR LAB. >> ALL RIGHT, WELL, THANK YOU VERY MUCH AND THANK YOU TO ALL THE PRESENTERS FOR AN OUTSTANDING JOB. HAPPY HALLOWEEN!