CERUS MEDICAL PRELIMINARY ASSESSMENT ((B)(6) INITIAL REPORT): THE ADVERSE EVENT REPORT (AER) DESCRIBES A CASE OF AN (B)(6)MAN WHO SUFFERED AN ACUTE REACTION 35 MINUTES AFTER INITIATING AN APHERESIS PLATELET TRANSFUSION (SYMPTOMS INCLUDED FEVER (39.5 ?C); HYPERTENSION (BASELINE 130/80 MMHG; POST REACTION 158/69 MMHG); TACHYCARDIA (BASELINE 78/MIN POST REACTION 148/MIN); SHIVERING; AND DYSPNEA). BACTERIAL CULTURE OF THE RESIDUAL COMPONENT AND PATIENT APPARENTLY REVEALED KLEBSIELLA PNEUMONIAE WITH AN IDENTICAL ANTIBIOTIC RESISTANCE PROFILE. THESE FINDINGS ARE IN KEEPING WITH A SEVERE SEPTIC TRANSFUSION REACTION. IN CONSIDERING THE RELATEDNESS TO TRANSFUSION, IT IS PLAUSIBLE THAT THE CONTAMINATION OF THE PLATELET PRODUCT OCCURRED AFTER THE STERILE INTEGRITY OF THE COMPONENT WAS COMPROMISED BY "SPIKING" THE BAG FOR TRANSFUSION, AND CONTAMINATION OCCURRED BY RETROGRADE FLOW FROM A BACTEREMIA IN THE PATIENT. THE PATIENT IN THIS CASE WAS AN ELDERLY MAN ((B)(6) ON RECENTLY-INITIATED, HIGH DOSE STEROID THERAPY (SPIRICORT 50MG). A SUBCLINICAL URINARY TRACT INFECTION WITH KLEBSIELLA PNEUMONIAE IS PLAUSIBLE, DESPITE THE LACK OF SYMPTOMS PRIOR TO TRANSFUSION, AND WAS NOT RULED OUT. THE FOLLOWING FACTORS FAVOR THIS INTERPRETATION: ? THERE WAS A 6 HOUR DELAY BETWEEN SPIKING THE COMPONENT AND BACTERIAL CULTURE SAMPLING. THE DELAY WOULD HAVE ALLOWED BACTERIAL GROWTH IN THE PLATELET COMPONENT IF IT WERE CONTAMINATED AT THE TIME OF SPIKING FOR TRANSFUSION. ? THE CONCENTRATION OF KLEBSIELLA PNEUMONIAE WAS LOW AT THE TIME OF SAMPLING. THE MICROBIOLOGY REPORT STATES A FINDING OF "+/- CELLS, NEGATIVE MICROORGANISMS" AND THE LABORATORY SOP CONFIRMS THAT A GRAM STAIN IS ROUTINELY PERFORMED. GRAM STAINING HAS A SENSITIVITY TO DETECT BACTERIA AT CONCENTRATIONS OF >10^5 CFU/ML. A NEGATIVE RESULT IMPLIES A LOW CONCENTRATION (
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THIS ADVERSE EVENT REPORT (AER) IS A REGULATORY AUTHORITY CASE SENT BY (B)(6) TO CERUS ON (B)(6) 2015 (ORIGINALLY REPORTED TO (B)(6) 2015) AND CONCERNS AN (B)(6) MALE PATIENT AT THE LUZERNER KANTONSPITAL WITH THROMBOCYTOPENIA AND ANEMIA OF UNKNOWN CAUSE (DIFFERENTIAL DIAGNOSES: IMMUNE THROMBOCYTOPENIA, MYELODYSPLASTIC SYNDROME - MDS). PATIENT WAS SCHEDULED FOR AN EAR-NOSE-THROAT SURGERY AND RECEIVED ONE PLATELET CONCENTRATE (PC) UNIT ON "(B)(6) 2016" (10:30 H) PROPHYLACTICALLY. PLATELET COUNT PRIOR TO TRANSFUSION WAS 33G/L AND POST TRANSFUSION WAS 62 G/L. SURGERY WAS CANCELLED DUE TO SEVERE TRANSFUSION REACTION (TR) CHARACTERIZED BY THE FOLLOWING SYMPTOMS: CHILLS, FEVER (39.5 ?, DYSPNEA, RISE OF BLOOD PRESSURE (BASELINE WAS 130/80 MMHG POST TRANSFUSION 158/69 MMHG) AND TACHYCARDIA (BASELINE 78/MIN POST TRANSFUSION148/MIN). TR STARTED AT 11:05 HOURS AND LASTED UNTIL 16:10 HOURS ON (B)(6) 2015. BLOOD CULTURE OF THE PATIENT AND THE CULTURE OF THE EMPTY BAG OF THE PC (RECEIVED BY THE MICROBIOLOGY LABORATORY AT 16:32 ON (B)(6) 2015) GREW AMPICILLIN AND CEFUROXIME RESISTANT KLEBSIELLA PNEUMONIAE (SAME ANTIBIOTIC RESISTANCE SENSITIVITY PATTERN) AFTER BEING INCUBATED FOR 10.5 HOURS. SAMPLE FOR PLATELET BAG CULTURE WAS TAKEN ACCORDING TO INTERNAL SOP- IN THIS CASE 10-20 ML OF PLATELETS WERE EXTRACTED FROM THE TRANSFUSION BAG IN A STERILE MANNER AND WERE TRANSFERRED TO THE CULTURE BOTTLES, THE REMAINDER OF THE SAMPLES WERE KEPT IN THE FRIDGE AT 4 DEGREES CELSIUS. THE SAMPLE WAS TAKEN FROM A PRIMARY BAG VIA STERILE PORT. THE PATIENT DID NOT SHOW ANY EVIDENCE OF SEPSIS BEFORE TRANSFUSION, OR EVIDENCE OF PNEUMONIA OR OTHER LOCAL INFECTION CAUSED BY KLEBSIELLA SPP. A BLOOD CULTURE WAS NOT PERFORMED BEFORE TRANSFUSION. THE HOSPITAL HAD NOT OBSERVED ANY SEPSIS CASE OF THE SAME KLEBSIELLA SPP. STRAIN IN 2015. THE PATIENT WAS TAKING SPIRICORT 50 MG (PREDNISOLONE) SINCE (B)(6) 2015 AND RECEIVED THE FOLLOWING MEDICATIONS POST TRANSFUSION: AN ANTIBIOTIC (UNKNOWN DRUG), TAVEGYL (CLEMASTINE) 2 MG I.V., SOLUMEDROL (METHYLPREDNISOLONE) 40 MG SINGLE SHOT I.V. THE PC CAME FROM A DOUBLE PLATELET APHERESIS COLLECTION DONATED ON (B)(6) 2015 BY A (B)(6) FEMALE DONOR (WITH A PAST HISTORY OF APHERESIS AND FULL BLOOD DONATIONS) WHO WAS FULLY ACCEPTABLE FOR DONATION ACCORDING TO THE GUIDELINES/SOPS FROM THE BLOOD SERVICES IN SWITZERLAND. COLLECTION WAS PERFORMED WITH A BLOOD CELL SEPARATOR TRIMA ACCEL (TERUMOBCT ) AND SPECIFIC BAGS TO COLLECT PLATELETS AND PLASMA (TERUMO SET NR. 80 410). DONATION ENDED AT 10:25 HOURS, LASTING 64 MIN. TWO SETS OF PLATELET COMPONENTS (PC1 AND PC2) WERE SEPARATED PRIOR TO SEALING THE SMALL VOLUME PI-SETS. STERILE CONNECTIONS WERE PERFORMED WITH TSCD II (STERILE DOCKING DEVICE TERUMOBCT); CONNECTIONS WERE CHECKED AND CONTROLLED ACCORDING TO SOP. THE FINAL PRODUCT WAS KEPT ON TC-FLAT INCUBATOR UNDER AGITATION AND CONTROLLED TEMPERATURE -PRODUCTS WERE KEPT UNTIL TRANSFUSION ON (B)(6) 2015 AT 10:30 H, I.E. 4 DAYS AND 17 HOURS AFTER TREATMENT (119.5 HOURS [5 DAYS] AFTER COLLECTION). ALL PERSONNEL IN CHARGE HAD NOT REPORTED BEING SICK. THE TIME BETWEEN DONATION AND PATHOGEN INACTIVATION WAS 6 HOURS. DONOR WAS NOT SICK PRIOR AND POST DONATION. A TELEPHONE CONTROL CALL DID NOT REVEAL ANY ILLNESS POST DONATION. THERE ARE NO PREVIOUS REPORTS OF TRANSFUSION REACTIONS FROM THE RECIPIENTS OF BLOOD COMPONENTS FROM THIS REPEAT DONOR. THE SECOND PC (PC2) WAS TRANSFUSED TO ANOTHER PATIENT ON DAY 5 AFTER COLLECTION WITHOUT ANY DOCUMENTED TRANSFUSION REACTION; HOWEVER, THAT PATIENT WAS ON ANTIBIOTIC THERAPY DUE TO HIS UNDERLYING DISEASE. CULTURE OF THE PC2 BAG WAS NEGATIVE: NO GERMS/BACTERIA COULD BE DETECTED. THE PLASMA OBTAINED FROM THIS DONATION WAS ALSO TESTED, NO BACTERIA COULD BE FOUND. INITIAL REPORTER'S ASSESSMENT (BLOOD CENTER PHYSICIAN: DR (B)(6), FREE TRANSLATION FROM GERMAN BY DR. (B)(6), GERMAN-SPEAKING CERUS MEDICAL REVIEWER): THE BLOOD CENTER PHYSICIAN ASSESSED THE RELATEDNESS OF THE EVENTS OF CHILLS, FEVER, DYSPNEA, INCREASED BLOOD PRESSURE, TACHYCARDIA AND SUSPECTED SEPTIC TRANSFUSION REACTION AS "PROBABLE" TO THE IBS TREATED PLATELET COMPONENT. INVESTIGATION OF ALL STEPS OF PRODUCTION DID NOT SHOW ANY NON-CONFORMITIES. STORAGE RECEIPT CONTROL OF ALL CRITICAL MATERIAL USED AND ADDITIONAL CONTROL OF ALL CERTIFICATES WITH SPECIAL EMPHASIS ON STERILITY PROOF, DID NOT FIND ANY NON-CONFORMITIES. TEMPERATURE CONTROLS OF STORAGE ROOMS, USED MATERIALS, INTERIM AND END-PRODUCTS WERE EQUALLY CONFORMANT. THE DONOR WAS FULLY ACCEPTABLE FOR DONATION ACCORDING TO GUIDELINES OF THE SWISS BLOOD SERVICES AND DID NOT GET SICK AFTER DONATION. MICROBIOLOGIC INVESTIGATIONS SHOWED BACTERIAL GROWTH OF KLEBSIELLA PNEUMONIAE FOR PC1. FOR PC2 AND PLASMA, NO BACTERIAL GROWTH WAS DETECTED (SEE NOTIFICATION TR NR. TR-1286). THE HIGH NUMBER OF BACTERIA DETECTED IN PC1 IS ESPECIALLY ASTOUNDING. TIME TO POSITIVITY WAS 10.6 HOURS (WHICH IS THE TIME GAP FROM PLACING THE BLOOD CULTURE BOTTLE INTO THE AUTOMAT AND A POSITIVE SIGNAL AND CORRELATES...
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ON (B)(6) 2016, DR. (B)(6), A (B)(6)-SPEAKING CERUS MEDICAL REVIEWER, CONTACTED THE BLOOD CENTER PHYSICIAN (DR (B)(6)) AND SHARED WITH HER ALL THE INVESTIGATION FINDINGS DESCRIBED IN THE ABOVE NARRATIVE. ON (B)(6) 2016, CERUS RECEIVED INFORMATION THAT THE BAG USED IN THE PATIENT'S TRANSFUSION WOULD BE SENT TO CERUS. ON (B)(6) 2016 CERUS ((B)(4)) RECEIVED THE FOLLOWING ITEMS FROM THE (B)(6): ONE EMPTY INTERCEPT PLATELET COMPONENT (PC1) BAG ASSOCIATED WITH THE POTENTIAL TRANSFUSION REACTION (TR); 1 PLASMA BAG CONTAINING RESIDUAL PLASMA (NOT PATHOGEN INACTIVATED) FROM THE SAME DONATION AS PC1, AND 3 BACTERIAL CULTURE VIALS ((B)(6)). (B)(6) ISOLATE WAS RECOVERED FROM A RECTAL SWAB TAKEN FROM THE DONOR APPROXIMATELY SIX WEEKS AFTER THE IMPLICATED PLATELET DONATION. (B)(6) ISOLATE CAME FROM THE PLATELET RECIPIENT ((B)(6) MALE PATIENT). (B)(6) ISOLATE CAME FROM THE IMPLICATED INTERCEPT PC BAG (PC1). THE (B)(6) STATED THAT PRIOR TO SENDING THE EMPTY BLOOD BAG (PC1) AND PLASMA BAG TO CERUS THEY HAD PERFORMED A BACTERIAL CULTURE ON EACH BAG, AND THESE WERE CULTURE NEGATIVE. ON (B)(6) 2016, FURTHER WRITTEN INFORMATION WAS RECEIVED FROM (B)(6). TRANSLATION INTO ENGLISH WAS PROVIDED BY DR. (B)(6), A CERUS MEDICAL REVIEWER FLUENT IN (B)(6). THIS UPDATE INCLUDED A MATERIAL VIGILANCE REPORT AND RESULTS OF A MICROBIOLOGY INVESTIGATION. THE MATERIAL VIGILANCE REPORT CONCLUDED THAT THE (B)(6) FEMALE DONOR OF THE IMPLICATED COLLECTION HAD A HISTORY OF 61 PRIOR APHERESIS AND WHOLE BLOOD DONATIONS, AND WAS AN ACCEPTABLE DONOR ON THE DAY OF DONATION, ACCORDING TO THE GUIDELINES OF THE (B)(6) BLOOD SERVICES. A TELEPHONE INTERVIEW DID NOT REVEAL POST DONATION ILLNESS. THERE WERE NO ABNORMALITIES NOTED DURING, OR AFTER DONATION. NEITHER THE PHLEBOTOMIST, NOR THE NURSING STAFF INVOLVED IN THE PLATELET COLLECTION REPORTED ILLNESS. A BLOOD BANK INVESTIGATION OF ALL PRODUCTION STEPS DID NOT SHOW NON-CONFORMITIES. STORAGE OF ALL CRITICAL MATERIAL WAS APPROPRIATE AND CONFORMANT. TEMPERATURE CONTROLS OF STORAGE ROOMS, OF MATERIALS USED, AND ALL THE INTERIM AND FINAL PRODUCTS WERE EQUALLY CONFORMANT. MICROBIOLOGY INVESTIGATION CONSISTED OF CULTURE OF THROAT AND RECTAL SWABS TAKEN FROM THE PHLEBOTOMIST AND DONOR, AND A URINE CULTURE AND BLOOD CULTURE FROM THE DONOR. PREVIOUS MICROBIOLOGY INVESTIGATION HAD SHOWN NO BACTERIAL GROWTH FOR PC2 AND PLASMA BAG. ALL CULTURES FROM THE PHLEBOTOMIST WERE NEGATIVE FOR KLEBSIELLA PNEUMONIAE. BLOOD AND URINE CULTURES OBTAINED FROM THE DONOR WERE NEGATIVE. THE RECTAL SWAB FROM THE PC DONOR, CULTURED UNDER CONDITIONS THAT WOULD FAVOR ONLY THE GROWTH OF GRAM NEGATIVE BACTERIA, SHOWED GROWTH OF A K. PNEUMONIAE STRAIN. ANTIBIOTIC SENSITIVITY PROFILE DEMONSTRATED THAT THIS KLEBSIELLA STRAIN WAS SENSITIVE TO ALL ANTIBIOTICS TESTED WITH THE EXCEPTION OF AMPICILLIN. THREE K. PNEUMONIAE STRAINS (FROM THE PATIENT'S BLOOD CULTURE, EMPTY PLATELET BAG OF THE TRANSFUSED PLATELETS ([TK1, AKA PC1] AND DONOR'S RECTAL SWAB) WERE ANALYZED BY PULSED-FIELD GEL ELECTROPHORESIS AFTER SUBJECTING TO THE XBAL RESTRICTION ENZYME. A COMPARISON BETWEEN THE BLOOD BAG (PC1) AND PATIENT'S BLOOD CULTURE ISOLATES SHOWED A SIMILARITY OF 97.2%. HENCE, BOTH ISOLATES WERE CONSIDERED ASSOCIATED. THE RECTAL SWAB ISOLATE FROM THE DONOR DIFFERED FROM THE OTHER ISOLATES (SIMILARITY ~ 40.3%), SHOWING THAT THE DONORS' RECTAL SWAB ISOLATE WAS NOT RELATED TO THE PATIENT AND DONOR PC ISOLATES. BASED ON THE RESULTS OF THE MATERIAL VIGILANCE REPORT AND THE MICROBIOLOGY INVESTIGATION, DR (B)(6) CONCLUDED THAT THE DONOR COULD BE RULED OUT AS SOURCE OF THE PC CONTAMINATION, AND THAT RETROGRADE CONTAMINATION OF THE PC BY CONTAMINATED BLOOD FROM THE RECIPIENT, WAS THE MOST LIKELY CAUSE OF THE PC UNIT CONTAMINATION. ON (B)(6) 2016 THE MICROBIOLOGY DEPARTMENT AT CERUS REPORTED THE RESULTS OF THE INVESTIGATION CONDUCTED WITH THE BAGS AND VIALS RECEIVED ON 05-FEB-2016. THE INVESTIGATION INCLUDED: PREPARATION OF INITIAL BACTERIAL STOCKS; GROWTH KINETICS IN NON-SELECTIVE MEDIA; CONFIRMATION OF BACTERIAL IDENTITY BY 16S RIBOSOMAL DNA AND BACTERIAL MEMBRANE FATTY ACID METHYL ESTER (FAME) ANALYSIS; ANTIBIOTIC SUSCEPTIBILITY TESTING; PATHOGEN INACTIVATION STUDIES; AND ASSESSMENT OF GROWTH KINETICS IN PLATELETS SUSPENDED IN ADDITIVE SOLUTION (PAS-3). THE EMPTY INTERCEPT PLATELET BAG (PC1) AND THE CONCURRENT PLASMA BAG FROM THE IMPLICATED DONATION WERE CULTURED AND FOUND NEGATIVE FOR BACTERIAL GROWTH, CONFIRMING THE RESULTS OBTAINED BY THE (B)(6) BLOOD BANK. THE 3 VIALS ((B)(6) [ISOLATE FROM A DONOR RECTAL SWAB]; (B)(6) [ISOLATE FROM RECIPIENT/PATIENT]; AND 61215 [ISOLATE FROM PC1]) WERE CULTURED AND ALL TESTED POSITIVE FOR KLEBSIELLA PNEUMONIAE (CONFIRMED BY DNA AND FAME ANALYSIS). BACTERIAL STRAINS DEMONSTRATED DIFFERING GROWTH KINETICS WHEN GROWN UNDER IDENTICAL CONDITIONS IN NON-SELECTIVE LIQUID MEDIA (LB BROTH). PATIENT (ISOLATE (B)(6)) AND PC BAG (ISOLATE (B)(6)) STRAINS SHOWED AN IDENTICAL GROWTH PATTERN, WHILE THE DONOR RECTAL SWAB STRAIN (ISOLATE (B)(6)) REVEA...
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ON 7-APR-2016 CERUS RECEIVED ANOTHER SAMPLE OBTAINED FROM THE PC DONOR (2ND RECTAL SWAB SAMPLE). ON 18-APR-2016 CERUS' MICROBIOLOGY TEAM REPORTED THE RESULTS OF THE ANTIBIOTIC RESISTANCE PROFILE TEST CONDUCTED BY MQA (SAME LAB THAT PERFORMED THE PREVIOUS ANTIBIOTIC RESISTANCE PROFILE TESTS FOR CERUS). THE RESULTS MATCHED THOSE OBTAINED BY THE (B)(6): SUSCEPTIBLE TO ALL ANTIBIOTICS TESTED WITH THE EXCEPTION OF AMPICILLIN (RESISTANT). THIS ADDITIONAL INFORMATION PROVIDES FURTHER CONFIRMATION OF PREVIOUS CONCLUSION BY CERUS. THE COMBINED INVESTIGATIONS BY THE (B)(6) AND CERUS SHOWED NO EVIDENCE OF NON-CONFORMITY FOR THE IBS PROCESS OR FAILURE OF THE SYSTEM. CERUS CONCURS WITH DR. (B)(6) ASSESSMENT THAT THE AVAILABLE EVIDENCE SUGGESTS THAT THE TRANSFUSED INTERCEPT-TREATED PC COMPONENT (PC1) WAS NOT THE CAUSE OF THE PATIENTS' TRANSFUSION REACTION, ALTHOUGH CAUSALITY CANNOT BE CATEGORICALLY EXCLUDED. IT IS MORE LIKELY THAT THE PATIENT WAS SEPTIC WITH K. PNEUMONIAE PRIOR TO THE TRANSFUSION, AND CONTAMINATION OF THE PC BAG OCCURRED BY RETROGRADE CONTAMINATION OF THE PLATELET CONCENTRATE BY THE RECIPIENT'S BLOOD AFTER THE INTEGRITY OF THE COMPONENT HAD BEEN COMPROMISED AT THE BEDSIDE.
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ON 7-APR-2016 CERUS RECEIVED ANOTHER SAMPLE OBTAINED FROM THE PC DONOR (2ND RECTAL SWAB SAMPLE). ON 18-APR-2016 CERUS' MICROBIOLOGY TEAM REPORTED THE RESULTS OF THE ANTIBIOTIC RESISTANCE PROFILE TEST CONDUCTED BY MQA (SAME LAB THAT PERFORMED THE PREVIOUS ANTIBIOTIC RESISTANCE PROFILE TESTS FOR CERUS). THE RESULTS MATCHED THOSE OBTAINED BY THE (B)(6): SUSCEPTIBLE TO ALL ANTIBIOTICS TESTED WITH THE EXCEPTION OF AMPICILLIN (RESISTANT). THIS ADDITIONAL INFORMATION PROVIDES FURTHER CONFIRMATION OF PREVIOUS CONCLUSION BY CERUS. THE COMBINED INVESTIGATIONS BY THE (B)(6) AND CERUS SHOWED NO EVIDENCE OF NON-CONFORMITY FOR THE IBS PROCESS OR FAILURE OF THE SYSTEM. CERUS CONCURS WITH DR. (B)(6) ASSESSMENT THAT THE AVAILABLE EVIDENCE SUGGESTS THAT THE TRANSFUSED INTERCEPT-TREATED PC COMPONENT (PC1) WAS NOT THE CAUSE OF THE PATIENTS' TRANSFUSION REACTION, ALTHOUGH CAUSALITY CANNOT BE CATEGORICALLY EXCLUDED. IT IS MORE LIKELY THAT THE PATIENT WAS SEPTIC WITH K. PNEUMONIAE PRIOR TO THE TRANSFUSION, AND CONTAMINATION OF THE PC BAG OCCURRED BY RETROGRADE CONTAMINATION OF THE PLATELET CONCENTRATE BY THE RECIPIENT'S BLOOD AFTER THE INTEGRITY OF THE COMPONENT HAD BEEN COMPROMISED AT THE BEDSIDE.