市販後調査及び観察研究の報告① OSSELAER ET AL. BL000 00MPONENTS A prospective observational cohort safety study of 5106 platelet transfusions with components prepared with photochemical pathogen inactivatlon treatment Iean C. Osselaer,Nathalie Messe,Tor Heruig,Iose Bueno, Emma Castro, Aurora Espinosa, Patrizia Accorsi, Kaus Junge, Michele Jacquet, JocelyneFlament, and Laurence Corash n late 2002 a photochemical trearment (PCT) process(INTERCEPTBlood Systems,Cerus Europe I BV leusden, Netherlands) for inactivation of pathoI -L gens and white blood cells that may contaminate platelet (PUf) components receivedCE Mark registration and becme availablefor routine usewithin certain European countries. During the clinical development of tllis technology, mndomized controlled trials were conducted in selectedpatient populations ftequently supported with PLI transfusions during periods of thromboci'topenia.''z By necessityfor conduct of the clinical tliats, these studies primadly enrolled patiens with hematology-oncology disorders.The tria.lsfocused on posttransfusion PLI count incrementsr and on assessmentsof hemostatic efficacvin f MATERIALS AND METHODS ABBBEVIATIONS: DSMB = data ahd satety monitoring board; HPC(S) = hemovigiluce plan coordinator(s); PCT = photochemical tleatment. Flom the Blood ltilsfusion Center, Clitriques Universitates de Mont Godime, Universitd Catholique de tpuvain, Yvo[, Belgiw; Haukeland Univarsity Hospital, Bergen, Notray; Centlb de Tlmstusidn, Cru Roja Espa-fiola,Maddd, Spain; St Olav Hospital, Tlondhelm, NoNa)4 Crntro Tlasfusionale, Ospeda.ledi Pescda, Pescara, ltaly; Omega Mediation, Offenbach, Gemany; Tlansfu sion Thelapies, Bdter H€althcare, Nivelles, Belgiu; and Medical Mairs, Cerus Corp., Concord, . California, Addr5s reprint reques6 lor Lauence Corash, MD, Medical Affai$, Cerus CoD.,24ll Stuwell Drive, Concord, C.\94520; e-mail; [email protected], Supported by research g!et6 from Cerus Corp. Disclosures: tocelFe Flament was o employee of Bder Healthcare Cory. duihg conduct of the study, Iauence Corash was atr employee ofC€rus Corp. duing conduct ofthe study. Received for publication April 16, 2007; rcvisioD received December 3, 2007, and accepted DeceDber 6, 2007, dol 10.1rll/j.1537-2995.2008.01643.x TRANSEUSION 2008;48:l06l '1071 Volum●48.」une 2008 TRANSFuS10N 1061 studyd€slgn General Blood trmsfusion cbnters with the INTERCEPT Blood Systdm for PLIs.for routine production of PLI components were invited to participate in this study. Patients in clinica.lcare institutionswho receivedPIJIsprepued with PCTwere specificallymonitored for adversehealth efects for 24 hours after each umsfusion; however,tlere was no time limitation on.reporting adverseevents after uansfusion, The sole lnclugion criterion for enrollment ms receipt of at least one PUf component prepared with PCT: Patientswho receivedPLI transfusionsadministered in an outpatient clinic were obseruedfor approximately 6 hours after trmsfusion and assessedbefore discharge. Study persomel contacted outpatient umsfusion recipients the following day to complete t}le.assessmentwith the standud data record fom. There were no other inclusion or exclusion cdteria. Patients in this study received only PLI components prepared with pathogen inactivation ueatment. The study ms designed as a prospective, singie cohort observational study to be comistent with European Hemovigililce Network recommendations for surveillance of advdrse leactions to tlusfusion of labile blood components and with those of lational trmsfusion 1062 TRANSFUSIONVolume,48, June2008 seruices.ss Study centersuansfusing PLI components prepared with PCT for pathogen inactivation 0NTERCEPT Blood System for Platelets) in rcutine clinical practice were requ€sted to complete a repon for each PLI transfusion regardless.of whether or not an adverse event occured following transfusion. Tmnsfusions associated with serious adverse events were repotted in greater detail, Patients were assigned a center specific study number to preserueanonymiry Conduct of tha study In each study center blood transfusion seruice,hemovigilance plan coordinators (HPCS) were designated as responsiblepersonsfor the conduct of the hemovigilance plan and coordinated all the related activides on site. These HPCs,with expertise in transfusion medicine, were responsiblefor oversightof data collection,ensuringdata completion, reviewing assessmentsfor relation to PLI transfusion, and completion of reporting information on any adverse event after PLI transfusion regardless of potential relation to the transfusion. Before initiation of the sudy, clinjcal care personnel were trained to the studyprotocol andthe specificform for data collecdon.For eachstudy PLI component issuedfor transfusion, a specific transfusion report form was issued with the PLI component (Fig. l), This form was eomFleted by the primary care physician and returned to the HPC in the blood center.Theprimilycarc attending physician was responsiblefor assessingthe relation of.adverse events to the PLI transfusion. The HPC reviewed the completed forms md contacied tlie prinary carc physician if data were incomplete or assessmen6ofrelation did not match the reported clinical data. The HPC had accessto patient medical mre recordsto query Emsfuslon reports.The ultimate decision for assessmentof the relation of adverse even$ to the PLT uansfusion was the resoonsibilitv ofthe primarytrcating physician. HPC6were chdged with popu. ladngthe database,by completingelectronicdata entry.In centerswheie electronic data entrywas not possible,paper forms were submitted and a sponsor representativa:populated the database The active HPCSwere Dr P Accorsi, Pescila ltaly (Site02); Dr J.L. Bueno, Madrid Red Cross, Spain (Site04); Dr A. Espinosa, Tlondheim, Nomay (Site03); DrT. Heri'ig, Bergen,Noruay (Site08);and Drr.C. Osselaer, Mont Godinne,Belgium(Site0l). A data and safety monitoringboard (DSMB) ms con. stituted to rcview the studyprotocol and provide oversight of the study.The DSMB reviewed an inteTim ilalysis of the data after 2500transfusions and the final report after 5106 Eansfusions, Study ropon lorms The report form used for this study wu dweloped on the basis of hemovigilance rcport forms a.lreadyin use and ｍト BACKGFOUND: lnactlvationol palhogensand whlte blood cells.inplatslet(PLT)componentswith ame toslen and UVA light (INTEFCEPT,Cerus EuropeBV) has enteredclinicalpractlcsin Europeanblood centers. A prospeclivecohon study was implementedto characterize the safety profileol thls new PLT @mponenlin a broad patienl population. STUDY OESIGNAND METHODS:Apheresisor butfycoal PLT componentswer€ leukoreduced,suspended In approximately35 per@nl plasmaand 65 perceni PLT additivesolutlon,and tr6atedwilh me INTERCEPT prccess. Blood centeG were requestedto completea safety dala lom atter €ach l€nslusion, RESULTS:Data for 5106 INTERCEPTcomponents sdministeredlo 651 oatienlswere monilored.A lotal ot 5051 (98.9%)transtusionsand 609 (93.5%)pationts had no reporled reaclions.Fitty-five(1.1%)lranstusions w€re assoclatodwlth adve€e ev6nts,and 42 (0.8%) were possibly,probably,or relatedto lhe PLT transtuslon. Advers8evenls occurredin 42 (6.470)palients, but in only 32.(4.9%)patientswas a causalrelationshlp to PLT transfusionestabllshsd.One reaclionwas' sedous,and no dealhswer€ relaledto PLTtranstusion. Among lh6 transfusionsreactions,th€ most frequent clinicalevents in descendinglrequencywere chills, fever, dermatologicreacllons,dyspnea,nauseaor vomIting,and hypotonsion.No episodesof lransfusionr'6laledacute lung injurywgre reporled. CONCLUSIONS:In this cohorl study,99.2percenlot lranslusionswere withoutreactionsattribuledto PLTS. INTERCEPTPLTSexhibllsda sdfetyprofilesimilar lo lhat previouslyreportedtor convenlionalPLT componenls. patients with relatively stable tfuomboc]4openia requiring iepeated PL;f transfusions.2Based on the design of these clinical ffials, the number of patients studied was determined by the statistical power required to assessthe primary endpoints. In the European trial of whole bloodderived bufli-coat PLI components' 52 patients received 3ll PCT PUI component transfusions. To assesshemostatic efficacy,a larger study was conduct€d in the United Statesin which 318 pauents received 2678 PCT PLT component uansfusions. In both studies ilatients were assessedspecifically for acute transfusion reactions for 6 hours after study transfusions and for other adverse events for either 72 or 28 daysr after the last study PLI transfusion. In both studies the incidence of acute tans. fusion reactions after receipt of photochemically treated PLISwas low and the safety profile was similar to that of conventional PLTs.s In general,prospectivestudiesretardingrhe saferyof PLI transfusion havebeen limited. The largestprospective PLI transfusion study before tht! SPRINTstudt'r was the TRAPstudy of PLT alloimmunization, which enrolled 533 patients treated with 6379transfusions,but this Studydid not specifically€emine safety,{After CE Mark registration ofthe INTERCEPTsystem,an observationalcohon safety study was im-plementedto prcspectively collect informa. tion on at least 5OO0PLT trmsfusions to extend the safery proflle of PLI components prepared with PCT administered to a broad patient popuJadon. SAFETY O「 PCT PLT COMPONENTS OSSELAER ET AL PLATELET TRANSFuS!ON REPORT Patient Sex:FO Age: DELAYEplTRANsFUS:oN ttEACI:ON RE'ORT lNTERCEPT P:atel● t Characterlstics and Transfusion M0 ; Ager Typel Hosplal name and cily` AphsGslsptatslets Rendoh-dbn;r ebreleG Characte&t6: O O R€porting Leucod€pl€l€d Olradialed Phm3d€pbt€d O Oth6r,spedfy Anlisgnmalded O _ R6portlng dat6 | BIood Bankid I:_____二 _二__ S6x Fロ M0 Reportingdalo I l'lospilalnamo and city i Reporternam6: し ocalonl l o MOdiCa1 0 1oU 0 sur9■ ●Utpa10nt 0 0,1可 _=___ Signature Start datg of the delayod transfusion r€action: Repoder name: Dat6 and time otlransfusionr Susp€ctsdor contlrmed dlaqnosis Slgmtor.l Did th€ prtlent sxpgrioncsany acut€advers€tnnstuslon rgactlonwithin 24 hoursaftertrangfugion? Yeg Et tl no, stophere No B ,ty€s : Startdat€andtimeol adversereaclion: ００ ● ted Proba,ソ Un70に P03SiOV Rolalod 0 g 'l O 2O 3 O ! D l60lal6d dysfunclion wihoul cllni€l Abg€nc€ of immodiale or longierm Long{emllfe{hroalening lmm€dlat€ lite{hBal€ning D6,th or blologlcal mantrgstatlon lif€-throatening SvmDtoms / Sion3 lmpubbtlltyorder) Products transfussd that can b€ related to thls event (bydocroaring ulじ Ю Spedfyt_=_______ u Drle ot transfu6lon Ciini● ●:siohs Afle. ° C TemperatuB Elood p6suB mmHg per min Pulse ll EI ND "c ONo E no mmHg O ND Q No Dor min E No Transfuaion.related laboratory abnomaliti€s 0 日 ooli籠 c血 口lo・ 日 add,unure口 IDae Bactqrioloslsalassgssments 1『 [i]よ lr`I よ Comments i]よ iraI l'∫ 握 Conclusion/Diagnosls/Additional examinstions(€.q.X.Rav... Please keop a copy of this report in the patient tile and do not forget to complote a 'loelayed Transtusion Roactlon Repgrt" it any delayed tranEfusion reaction occurg (e,9, GVHD, ...) 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ｏ 〓 ● ´ ● ● ● Ｌ ● ｏ ∽ ｏ ● ” ｏ ´ ヽ ・ ● ， ｏ う０， φ一 も ・ ● ●目 ●〓φ ″り 一 こ・ ８ ・ ｏＰ ， ，０ ●３３とｏう・ 一 ８６ ご潔 ＦＦ晏 ︵ 日翌Ｆ︶ ０ 一 Ｆ ，おお ﹁お ‘ＯｏＯ ざ ︻， ｏ ， ヽ¨うｏ一お 零Ｈ す０﹁つい０﹂ いｏＯ ●０，０くｏ﹁ ０﹁↓”ヽ■﹄ヽ＞ｂヽ０一 ●”一６一 ”一∽一 ●ｏ ①て ６●↓ ∽ Ｅ６ぉ ０●８ ８ 一 ，ｏ Ｆ ８ 一 ざ‘ 一一¨ ｏ自己 ｏＬ Ｏお ●一 ｏ● ↓すｏ ∂ 一 ′ ■ ｏお お ｏＯと ＱＯ げｏ♂ ３ ●●一 ｏ沖ｑ ｏ●ｏ， 一３ ， ど ａδ ｌ お ヨ ‘ ，＾ ，Ｆ Ｅｏ＆ ヽ８ｏ ｏ ●” ，こ 鷺” ， ３ ０ ぎ ０， １ ， 姜 ８ ｏ ■２メＰφす●´ ，σ●●” ヨ と ９，おＬ ごげ０計ざ 囀 くＬぼツ ヽ﹃３邑ａ ﹁ ● ¨ ● ０ す Ｏ ，“●０∽ ●●﹃ ０●０ ●●一 ｐヽ一 ｏ“■ ●一〓， ●●一 σ“ｏ一 ｏ︲ ● ｏ ｏ一”﹃ こ ｏ色言 ８■ ８ ３ 宮 静 ヨ 〓 ０げ一 Ｈ ８ Ｑ ８ ヨ罵 輛 ■ ８ ●８８ Ｑ ０ い ， 電０１ ” ８Ｒ ０ ｏヨ ｏ ３ｏ００Ｌ ３ｏ９ ０ ３ おいＥ 澪０ ８ なく ” すｏ ●０そ δ” で ６〓 ｏ一 ０くｏ●＾ ”０﹂ ” ０一 ｏＬｏ● 穴︶■，コ●つ” φ¨ ｏつ ＞ ぉ ● ２ お 〓 ｏ ●０ ョ ｏ●＾ ︻ 日 ，︺ 一一 ｏ■。ｏ３ ｏコ ヨすおプ ｐ●くｏこｏ ュ ａ プｅ，Ｎ●すｏ●Ｈ ●く０●● ●０２● ”¨ ■ 繁︶´ 一●かｏ﹁﹂，ｏ ●ｐ●２ピ・ Ｏｏ営● ¨ ０ ，゛●●＾ ｏ●・ ゛一 Ｏｏつ∽ ” ，●ｏ﹁ ●ｏ一 ０● ● ０●﹂と 。Ｌ“ヽｏｃ 一 ｏ●０， ＬＯ●´ 〓ｏ” Ｆｏｃくｏ●一”●０ ｏ” ｏつ０●０一〓〓〓ゃ００おＸ 一 ｏＯｑピお ﹂ ■ ＆ ， ０お一 ●●０﹁〓 ● ８ ， ■ ｏ■ ﹁﹃ ８ ヨ 一０●０〓 ︼ず０﹁ ︼ すｏ， ヽく０ 叶， ｏ ｏＬＯい０﹁＾ ﹃＾ ” 〇０ く 一 ｏ ●一一 ０，ｏ一ｒ 口ｏ ， Ｐ∽ 一 ︻ 一８３ａ 〓一 ，Ｉ 鮮ｏさ﹂ ０●■３ ｏ 一 ぃ 口∞８´ ２‘ ●●７ ｏ ￡ ｏ﹁ ０ぞ ■２こ２●３ ●ｏ，ごギ ︼ ︼ ｇヽ ８Ｆ８， つ” ｏσ， ２・， ヽヽ ｏ ｏσ● ︻ 一 ´ ” ＞●くつ 一 い０ ０ヽｏつｏ∽ σ一 ” ｏ ｏＬヽ０ ●﹂” ００・ ¨ ｏ ” ﹃ ０ ｏ ¨ ●ｏ くｏ ●一 ∽０ ● 一 ， ∽ ド げ一 Ｌヽ一 ↓ ﹁ 一 ０， ０げ” い●０ ｏ一 ｏ ｏＯ ″ ●０ ●∽ ｏ●´ ヽｏ ●、 ﹁ ﹃ ０一０ 卜ｏ■一 ∽汗 ﹃ ｏ 鰤ｏ ・ どｏ ぎ●おヽ ざ●，キ﹄ ｏ ＾ ざ，３●２一 お，●２６日ｒ営０一 日，ど一 ｏ●∽ ●ｏ Ｏ ，ヽ２，¨ ２ｏ ●ｏ Ｌａ Ｏく ，ｏ ェ●０ て お ヽ● くｏ ュ，ヨ ｏ ｏ ， ｏ ♂ ﹄９こ う¨ ｏＲ融も ” ¨ ０ ¨の︻ ●０●０” ●２ ２ ●０ ０マ●ど ●２ ざ ● ● Ｆ”ＯＦ ユヨ● ２ ０﹁ σ‘ざ 電０ ヨ Ｒ 亀 ８ ご ●ｏ■ ０３ 一ｏＰ１ １ ●。■ ，ｏｏ Ｒ ¨ ︼ お‘ ， 燿 ”〓 ュ ●” ョ ョ ｏ一¨ ■ ｏ ・・ ざ ・” ＾ ｑユ 一 ＯＳ ヽＯＮｌ一 一 貯， ５ ■ キ ｏこ ●” ｏ■８ ＾ ｏ郵器 ″¨ ｏ●Ｔ お ヽ ヨ 一 ● ｏ︻ お い“， ヨ＆一 静， 貯ｏ ヽ Ｒｏ ︼ ュ潔 ｏ 一 ｏ ■■● ， ● ”０ ０Ｓ ●ｏヽ“０●●５ ・ ンで Ｆ 〓，２ ・∞じＲＲ ■ ●●ｏご ａｏ● ロデｏお ■ ８ 一ｒ， ︹ド●■， ︵ ”８ ●ｏε ●う０ ﹁お ｏ，お α で ，， ”日 ｏ６ ●Ｌｏ●・ 〓ｏ一 ︵ 口ｏュ ョ Ｌ ＰＬｏ ■ ｃＳ ８ モｉ ３ ８０，〓 罵”０ ３ｏ ８日 き ｏ一 〓，■， ８７ヨ︶ｏ ８´ ３９■ＳＯ﹁ ｏ ８こｒ¨８ ，●〓〓‘智？ ，‘ｏＬ︵ 〓︻ ９． ｏ ，ｏ ５ｏ ６ ●燿 一 “●８ ●ｏ ”く、 早 ｏＲｏ﹂ ﹁﹃ ａ ｒ ξ ８ ｏ８ 甘 ■ ， おヨ〓 ︱ ８ ヨ電 〓 ●一 ζミ９” ｏ︻ ＾ ヽＮ︲Ｎヽ。 ０︶ ヽｏｏｏ●〓●¨ 一 Ｃ﹃０ ００●●０︼ ︵ ｏ ∽¨，●０，︻０ ●一ｏ一 ｏＬ，“ ｒ ，８ 〓 オ， ，摯 ざ ●２ ﹁﹃つ。ｏ，Ｃ﹃ｏ∽ ざ 一 ｏ・０す ｏｏ５８ ︻５ ０●Ｂ ●一 Ｌ Ｌ ， ” ０ ¨ じ ， ﹂ ︻ｃ“ ｏ ｏ﹁， す ＾ ●ｏ ９メ ● も，一 ｏ“ｏコ ´ ● ｏＬく，ＯＯ● ●ｏ●● ●る ， １ ０ ‘８ ０ す ０一 ２ ０９ ８ Ｌｏ● ８ ●３ ヽ ユ 〓 ｏ ユ σ汁 一■ ¨ げ，， ８ ︼ 巴 ８ ０■ ヨ ョ ヽＬｏ●●●ヽ， ■ ●Ｏｏｏき ヽヨ ヨ ■ ■，Ｑ一 ｏＬｏ● ♂ ヽ ﹁お ヽ 営 一 ざ つ ｏ﹁ 一 Ｓ ●いご ∽● ● ｏ参 ｏｏ¨ 猟 ００ 雪 ，Ｐ之 ●ａ ●で すｏ∽ のくゴ ０︶■ ﹂一ｏｏ●〓あ ｏる ０﹁＾り ０●０す■３ 一８∽●３ ｏ ︵ ヽ ２ ２■お ヽ 一●●ｏ， ・ｏｏｏ﹃０３ ” ８ 一Ｓ ●Ｑ”ａ ｏ﹁■ 贄 ， ” 一δ ｏｃａｒ器 ∽ 営 ０一 ６ す Ｏｏ● お ， ０ ●●ｏあ 〓 ＯＨＯ ●ｏ８ ●●●０ ，つ０ 一０髯 ００ 沖 ■ 曹 ●ざつ， ■●●゛ ０５” 一 ■●，゛ ヨ〓５０ ０，， ０∝ｏ●ｏ ，０００︻ ０ ●、ｏ〓 ８●０弩Ｏ ｏ﹁ｑ２， ¨ ﹁８ ｏｏＯＬ８ｏ ， ｏｏ日ヽ ●●ｏｏ ●ｅ■８ ． ｏｏ ０¨Ｌヽ●０●， と口 ００日 ヽ０●０●● ，■ゴ 翻僣 ｏｏ●くｏ ●ｏＬｏコＬ ヽ ‘ 嬌 ぉ ざｃ＾ｑ ｏ一一８ ３ ２手 ｑ げヽｐ●●﹂ｏ● ９ σくｏ８ｏ， ∽庁Ｆ 穴ｏ﹂ｏも一 ｏＬｏ●・ ﹁壺﹃ ｏＯ日一０●０●羹” ●〓， ︵ ｏｏ●″■うし，“ Ｎい× ︼ ¨ ”Ｅ″︶ ‘おお ‘ 一６ ｘ ” ●一 εヽ Ｆ一 ● ”●”” ｏこ﹁Ｓ一 ●０●●●一 ︻ 夢 ＞ 〓一 ａ●′ 二 多 ”３ ８ヨ一８ ８ ６ ■９ 一 ２ ９８ ，３ 多︼ ， ゃ０︼‘ｏ； ﹂Ｏ ヨ”，ｏ資ｒＯヽぃｏ日 ｏ ●８﹂。﹂﹃ ﹁ｏぉ０ゴ一 “ヨ０ ０９ ｏげｏ﹁ｒ ＮＯｏＰ 一 一ｐ 一一ｏ９ ５ コｏ ＯＵＯ一ｏま すｏ﹃一 ５０●ｏ●∽Ｌ¨ ●８ ” ご 〓 ｏ●２， お つｏ﹁二 ｏＬｏ● ｏ﹁， お ｏ■ 一メ ０くｑ ２一 一０●∞０■●口で ご ３つｏ お ｏｏ■∽ ６”ＯＳ︶■ｏ一 ｏ お０●ｏ一 守９日 Ｋ ｏ●一いｏ﹂¨ コ”● ”ュ咀ｃ● 一ヽ∞Ｎ ＾ 富５０ 智 ０８ ● ︻ ｏつｏ■一 Ｇ あＳ︶ やつヨ ”ｏ” ¨ｏ， Ｚｏ ２８く ぃ 、ま︶やｏ ０ヽ ｏ ″︵ こヽ ¨冨∞，Ｆ∽ ´一 ” ‘●” Ｏ・ も ζヽ り ＦａＦ ３一´ ﹃ ｏ さ ゃｏ コ一 日 ギ８針ｏ ，ュ憬 ぉ■， お、 ﹁ ＬК ＾ ｔ 一８棺曇 ざョ智∽ ｏ ● イ ョま ヽ ゛︼ ∽一 ｃａく ０“彙●ヨ一ＬＯコ´ ００﹁●０，一 ｏ● ン一 ０一 と ｏ﹁ｏｕ一﹁ｏＬｏ●， ” ｎｏ●い０●●●¨ 一 すｏ ●ｏ９で ６０ ，Ｐ‘´¨ 誼頭﹄絆鷺 調講配市 怖軒詳﹄ 一 巽 ﹁ ｒ﹁ “ヽ●ヨ０﹁こ●¨ ０ヨ ”一¨ ３ ●Ｑ ８ ８ ●コく∽ぉ ， コψ ｏ”一●〓 ０ ”Ｌ﹁ ｏｏ日 一●●ｏ●● ざ Ｈ 嗜、ョ Ｆ ゛一 ｏ・ ■ ８ Ｈε ●”ぎ 黎 ■ 一ギ ０ ¨ 一 〓 ●８ ， ・ｏ¨ ８” ●ヨ ■ 一 ， ３一 〓ｃＬｏ● ”ユＢ ﹂囀 ｏ●ぉ ﹁〓薔 〓 〓 ・りヽお りｏ け 。。 もお 嗜，●？ ﹁ ご ｏざ ● ヨ ｏ■ ｏ，●ｏ● ●ｑ 一８ＢＱ●︻Ｑ ｏ﹁ ｏ■ ９ ヽｏヽお ｔ ヽ■つ “ ¨ ョ ”く ｏ，３ ぜ，場 ぉご●● ヽＲｃ ︻ Ｌ 筍” Ｏｅ３∽ａｃ 一 ｏ４ ｏ一ｏ■ ヽ 機８ あ ♂︻”ｏ９δＯ ｏ︹Ｎ●，ｏ‘あ ，´臀 ｏｏｏ ”０くｏあｏすｏＬ， ｏ ゴ ●ｏ●資ピｏ一 ０ ” ´ ｏ● 〓■， Ｌ︼ ｏ ゛ ｐ●ら，” ｏ﹁ｏ■ ﹁ ｏ●日 ，ｏＬ ｏｏＬ一 ８一ｏ、 ８ ヽ，９た ｏ ︼ ∽●プ。Ｌ〓 ｏ浄 ｏ一 一 ∽，¨８ ，ｏ ●ξ ●３ 魯場﹂ ｏ● 多 ｏ日 ●ヨ ｏ〓８一 １︼ ３﹂０， ０一 ９■，〓ｏ“一●，●一 ヽ●０● ＞ αｏ， ﹂０一 ０冬 ●ｏＬｏこ ，ｏとヽ諄 ●″● ♂ ﹃＾ 〓ｏ，口ヽく，，∽“８ ， 一 ヽ口ぉ ０ ●●０ ，一一︻ ● ヽＥ ，ｏＬ●‘ｏ﹂ ｏ ０で６一 σＯぉ ３ ●，２ゝ” ３とヽ ３ ｏ・雀 ８ 日 ，ａ Ｆ σ一 ｏタト ●一０●６ デ 一 ８ ■， サ 錫 電０■ 零 ●９ ，一 Ｏｏ３ 一●８ ﹁一ス ョ ，お っ＞“ ざ ■︼ 贅 ニ ユ ｏ●晏 ｏ● ∞卜 ∽＞∽ ゴ ∽ Ｚの︶﹁ゴｏ﹁ユ５ ，囀 ｏ欧 ９ ∽ ョ ０●一■〓 ９ ｏ， εＯｏ，ｏｏｏら，ヽ●γ ご ●ざ ●３ ●一一●●∽﹃すｏ●●ヨ ０■ ，う００﹁ メ︶ｏ﹁■●う， ｏ●ｏ■ざ ｏ︵ き ０ざ●∽ ●●Ｏ ｏ﹁﹃ｏＬｏ﹁一 一 〓，す ｏ●ｏ ｏ﹁ ■５８ ●■ぁど 一ざ っ 嶽額纂鋒雛騨満 鐸鋼嚇期︸ 攣黎 ｏ嬌０ ぉぃヽＲ∽ ●３ｏ ︶︼ｒ●３， Ｌｏ 揚︵ ‘ュＣ●［ ヽ●“ ，Ａ︻ ０● ●● Ｒ ”﹃ 嗜■● ９ヽ ｒ￠ ０フ コ ●ｏ ８ｏ ユ，８∽ 一 ２ ¨ ヽ ８８ ，９﹁一 一 すｏ げ∽ 一 ｏ ニつつ´ ﹄” ﹁∽ ｏ ロ ●﹂ｒ●ｏ ” ︼ ● ●●２ ●● ヨ﹂ｏ ヽ０ ＾ 〓Ｌヽ短凛 ど８ ａヨ ヨ ＾ ８ ヨ﹁０●●●● 〓ｏさ Ｆ５ ｏ ｏａ すｏＳ ａ ﹂ユ ， ●●０一 Ｉ ﹄ ﹁ ｏつｏと ０●５ ０ｃＣ ●Ｌ８ 一３ ■ ９ ︵ ∽ デ ０お ■ 属ｏ■ ，＾ ９ ０要 つ●８ ︼ ０３ ３ 〓 ュ 摯 Ｒ ミ¨ ， ｏＦ 針 ｏａ ， Ｆ ４，要 ■ ，，ａげ Ｌ ｏ●● ヽ，ヽ ■る ０す２８ 〇一ｏこれ ︼ ｏｏ Ｏコ，３ ，９ ヽ０あ ｏ ｏく０●● いｏ 一●﹃ ，日魯●ｏ ” ， ６ 風８一 ●︰ ３● ●２て ｏ 苺 ヽ， 百 とく ″智ｏ 二∽ ８あ●●おコＬとでヽ ●〓一 ， ●● ｏ ３２，ｏ 〓０ ●ｏ ´ ｏ ・・ お， ？ ●０３ ´ お８８り０‘，ａ ま，日巳ＬＳ〓● ２●霊■ｏお” ″ ａ ８ ｏ ● 営 ■ ， Ｓ ヽ ｇ ヽ・∽ｏＯ一ｒ ¨ ｏ一∽〓 ●８ ● ■ ２ 一 ■ ８ ８ 一詩 ・ と い８ ●ｏｏ一 ｏく２・ ∪●” お お ，●Ｌヽ ＆ ｏ● ● ヽ①一＾ ｏで ｏ● ２ ● ●８ “ 目 ， ど ・一 ●´ ０●ＬＯ員 げ、一デ ３ ●ｏ﹁８ ■ 卜 ， ≧ 〓 Ｚ︼“”０口 ﹁ や■ ●●夕 ど ‘ 。 ０ざ 房 ，０３ ５ ¨ 一 ０８ ８ ６ ０営 ｏユ ｏ ■ Ｒ Ｏ ﹁ヽ● ０“ ， ０ ，Ｌ ｏ口とく゛ヨ 筍●●二 ， ６● ●●●●０■ ，コじヽ 。， 〓，ｏ， ｏ﹁ｏ﹁●９ ０● とお” る，８” ■３３３■８ ど︼ ８ 〓﹂ヽ ｏ ３■６３８●０許一 二，¨ 〓〓昌 ２ご∼一 ｏも〓こと３・ く０こヨ ｏ ，Ｐ ｃ，３０ ＮＯ︶０ ﹁”●２●﹁Ｃ∽一 〇 ２ ４０〇一 舞 一 鼓 いや “馨 ¨鰐 諫 攣 ¨麟 ♂ 中靭 ¨率¨” 畔 ﹁ 忠ュ＾ ∽ ６ ぃ０メ ︶ 口，Ｏ Ｌ ﹁ｏＲ ぐ ３ ｏｇ くｏＱ ，コｏ＾ ゴｏ一 ０●一 いＯＮ ●，＾ σ一 す０︹ げ●一一一 ｏｏら ｏ︻ ｏＯ‘０´σＯ沖■ｏ一 ｒヽヽ ¨ ﹁●●ｏ﹁‘い¨ ｏコ・〓Ｌｏ●日ヽ・ すｏ﹂¨■● ，ｏ Ｌｏ●” どＳＯ﹁〓弯ｏ﹃ ｏョぉ２●”∂﹁０〇一Ｒ３●メ ヽ■● つ０■ヽγ ゝ ヽ６●” ，ｏ ｏｏ 一 コ ” ︻ どｏ 一 δ， ＯＲぉ●ぉ ■¨ Ｓ，ｏ コン一 ぃつｏ Ｌｏ いヽさ︶¨ Ｏｏ ｏつ、、 ●＾ ｏ︵ 一 ぃ 一 ● メ ｏ っｏ ●“，■， ヽ コリ ， ０ 一ｏ” もｏ ご３ｏ ● ２８” ｏ一の ｏ ＬＯ●‘摯ゴ 一︻ ●﹂ ｏ３つご嘲０一 ざ﹃ ●ｏ 一 ゛ ｏ９， ぃ ａご∽ ｏ 口０﹁す。■ュ９一 一 ω ぃ 望 ■● ‘■９一口﹁８日●０ ●０ ■ｏ︵ ０ ● あＳ︶〓■ｏ， ０日，¨ ぉお０３ ﹁， Ｌｏ Ｑ巴〓” ｏ ０ヽ ●ａ ｔすｏ，， 一ｏ お８一 お０● けお 〓ｏＰ‘‘●一ヽ ●９ゴ■ｇｏ ｏ 日ヽ０ ， けｏ ●０ ｏ ●﹃ 一 ， ●ｏど ｏざ ●， Ｏω一 ０ ド 主 ご ３ ●ｏＦ Ｌｏ■ ヽ日 ６ ●” ， ９ ｏ 社 ”︻ ﹃ 一８ ヽ●ｏ， ■ ｏ﹁ｏ■，，一ど め０。５ ０●●ｏ，あ ︻ｏ●０■０〇 一 ０〓１ ０ ｏ者 ■ 一 ８ ８ 一 ■ ぉつ∽８ ３ ●３ 一ど 一︼ ８ ８ ８ ＬＯ● ５ ， ｏ Ｖ β ●５ ８暑 ０ ョ ■■ 場 ■ ３ コ ＞一 豊 ﹃ ｏも ヽｏ■ ｏ●Ｒ ， ｏ〓﹁ ８ ３●０●ｏ●″ 三０お ■●″ ″ 一 ＆ 〓ｏすｏ一●〓２ ｏ，一 ｏ●●ｏ●Ｆ一 ０●一 ｏ口，一 ａ﹂ヽｏ， ０雪貯ｏやＳ¨●●ヨ ， ュ一 おお一 ´ ０●●●ュ ｏぉ０ぉゞ︶■９ｏ ，。日 ¨ ● すｏ日 営００●Ｏｏぎ３ヽ 一 ■げＱＲ﹁● ´ ■●¨ ● ● ■，■， ｏ，ｏ ﹂■ｏ３８¨ ﹁ ごとい８ョ”“ 一 ″ 〓ｅ Ｏ ０ す¨８︻ ｇユニ８・ さ 〓ｏ ０ 一 ■ ８ヨ●Ｏ ３●●８轟０ ９ ， ” ぉ ． 。 。 ， 。 口 。 ﹁ ・ い ¨ヽ れ 都 純 ﹂ や ％ 中 ﹁ ” ¨ ﹃ ¨ ♂ ¨ ¨ ¨ ¨ い ﹁ 一 囀 ﹁ 一 靖巽 ｐ 残 誇 請 聾 灘 誓鍔訴 一い れ〓 識希経蹟 鍼¨ 凝 戴騨鍾 ﹂ 澪淡 露調 ¨ ”Ｌ﹁ ●“ ●９０ Ｓ︶ ●ユば，ｏ ピ ｏ ５０ｏ コぐ ●一 Ｑ くヽ り ●︼ ﹁ ︵ ｏ ヽ︻ ま 中 ｅｄ︼ ｏ 非 路 勇﹄ 委 鞠尋詳霙霙 舞 すｏ 共一 一 ｇ一 ，０９﹃う０， 〓，ｏ ●● 日ｏ ｏ ｏ ３・ 蠅翼お 〓コ３ ９一 ” ・・ｏ ■３一８α〓二〓げ●■３２ れｏ ¨ Ｌｏ 一 ●とマ¨ ヨｐ ８・ 曼 菫０ 評沖 鋪勇 羮 委 霙 諸 難 翼 一ｏ 一 ３ δ””鋼 ■， ，富゛ ｏ フ ‘ｑＱ∽ ｃ ｏ６ 賊 場富ｇぉ３フオヽ 藤話¨ 瞬針¨ 鴻調請婆野 雲輯轟¨ “ ， 〓 ｒ ， ︵ ， じ ｇ 髯 ｏ ｏ ，口ｔ ９ す０ヽ ●ｏｏＱ ｏュ ヽ ９９つｏお ｏ●一ｏ﹁︵ く，ｏｏ二 ，﹃一‘品 ９メ ” すｏ ８ 一 と 資 ０日 一 ■ 自 ● ●″口 ´ ●ｏ，， オ●一●０ ９Ｐ ︼●ｏ︻ｏＯ●´ ●“ ¨ゴｏ 〇２ ︻ 一ε“ ２ ︼ 〇 一す０︻ ｅ 爛 Ｂ ｏｏｏｏ ¨ ●ｏご Ｑ①Ｑ ｏ●﹃咀 ｏと 一 ●３ ２ ０●＾δ ●● つつ０一０‘﹃ ‘つｏｏ●ｏ一 ｏＯ´ ”●ｏ●０一 ●一 ｏｏＯ¨ ●”ヽ“●０ ∽ｏ﹁∽﹂ ∽ つｏ●●●一σ一 ｏｏｏｏ●０●迎■０︼ ｏＯ出ヾｏＯ■らｏｏＬｏ●， ョンロｒｍ 一・，，●●コ”Ｃ●ヨ ｏＱヽ０﹁〓一 ０● ，”〓ヽ ●一●一 ＥＱヽ “ ヽ●，０一 Ｃ●一 ０■ 繋覇瑳暉準トー■︱︱ ・ 膵 瑞 昭輸 ¨ ¨ 霙 一 σ ” 。 諾¨ 町黎ユ 一 ・ ・ 郷牲斃 ¨ 嬰 ・ Ｎ 調襲錯唯 一 摯当︶ ＞Ｏｏ︵ φ︶ くｏヽヽ ｏ“ ●長● ”ュ ０一 ０● ヽ ﹁ ０一■ ︻０● ａ Ｆ ａ ｏ● げ ｏＬ ， 贅︼ ●αＯ〓 ︼ｏ● ”すｏ ヽ ””﹁０●ヨ ●●●一コ一 ０●げヽｏ一すｏ く ｏて ０” ０●０〓０〇一 ︻ ｏあ一 Ｏｏヽσく´ ヽすｏ︼ ｏ げざ。一■げ〓く。。 σ●お ゃｏ曰 く２●つおｏ” ぞ６０ヽ一 ００００●３０ ０︻ コｍ∽Ｃｒ↓∽ ωいもｏヽ ００●一﹁一 ﹂﹂ｏ● 〇０●ｐ ● ，う０ 一Ｑ﹁ｏ” ＱＯ●一””﹃ ●ＱＱ汁一 くｏ ｏＯ︼ 一 ¨ ０さＯ Ｅ００コミ●８■一 ﹁ｏＬやＲ ●ｏヽ二，Ｌｏ● ０﹁ ８ ｏ﹁手 ｏ”目¨ ｏ 一﹃ ●●●魚澪¨ ｏ， ０﹁﹁ｒ﹃ ００コ″ 一〇３０●● ０ ●ｏ ”ｒ， “” ¨ ”﹁＞ ｒ ＺＯ●ユ０●●マｏｏ ●６ ｃユ¨ ωＯ一６９じ ェｏョって ｏ９ ︲ ３ ８ ｏＱ 罵 げ ヨ● ●ぶ ６一こ 腱麗扉器 雖 翼 ω れ頭︶ ↓ ¨ 、 く ・ ∽ ¨ 轄 一 一 睦 一 螂 一 一 ﹃ 一 ¨ 一 ﹃ ¨ 叫 い ０８●ｌ おう３ 一 ｏ全 じ ３一 。 ． ｏ ■ ・ 鵡螺 ¨ 鵠諏一 艶誇号８ ｏ ． 一ＯＣ﹁ｏ●一 ごう● す一Ｑョ″●コｏＱヽ●δヽｏｏ＾ 一 ＯＬヽ”８ ８ｏｏ■ｏＱ●●コｃヨσＲ ︵ ヽ﹀ “●００ Ｈ” ＞ ２ ０﹁Ｃ●一 〇 ２ くＯ Ｃヨ ０ 一● ﹂ｃつ０ い００ω ・ ｍＸ一 〇３″０﹁ＯＸ００●Ｃヽ ｏ ＯＬ Ｆ ”〓る ｏ０８ ■ ， 一 ｏ●ュ 一ｑ δ ■ ， ｏ３ ●”ｏＲ ，ｃＯヽ，一〓 ︲ ︵ ｒａｏ●●●ｏ︻ｏｏＬｏ●´‘”∽︼一０ ︼いＯ Ｆｉ︸ ●■５ｏ● ｏ﹁ド∝ ■ ︼ｏ● ■，●∽ご ‘ｏ●∽ヽｑ 一、ＬＯ●●ョ，ｏヨ ｏ２ ，，くと●ｏ■●ｏＮ●ｏ，●ご ︲ ０●ｏ 筍ｏ﹁も，●ｏｏ， ＞ ∽‘げｏ一 ∽¨ ，●Ｌと ﹁﹃ ０●ｏ﹃一ｏ● ｏ﹁一ヽ●０●¨ 一 ３０い ざ おｏ ﹂ ａ ︼ ｏ おαＦ〓０ ０” 局 ８ヨ一〇３●ａ ９ ヽ， デ げざ じ ︵ ”０く０ヽ゛０ ●く０３一， ０つＬ 〓●，０︹ ＣＬ Ｏ一 ヽｏ，０一一 〇３０ ●■●一 つｒ︻ ¨ ヽ ●●ｏ↓ ●●一 ０●● ０●ヽも０﹁Ｆ〓 ｏ ど∽ ざ●げ静 Ｆ 一いｏ﹁衝︼０一一 ヶ ●∽貧■夕一 ８，∽Ｆ ∽ ８ ざ ９ ０● ﹁ ａ ９ ９ ″卦 ｑ て ０︶扁 ８ ︻ ０〓 ︱ 一ュ ， ，含 ・Ｈ ´ ●︻ ﹁ ●２メどの ざ●，つＯωユ ´ ，３ ●６■ド︶〓９０お●●〓ｏヽ〓︼ ， ６●‘Ｒオｏあｏ９おコ〓 ﹁０■下コくｏ一 ｏ ●” Ｓ●亀ｒａｏ●ｏ３“メ一０いま Ｑ ヽ９８ ■ ︼一 ︶´ ８ と お短ｏヽ＆ ■ ， ａ ｇ ぶｏｏヽ ヨ ム ♂ げお ３ 一 ８ ６ ，ｏ■，≡● 一 ８〓しヽヽ ヽ ■ ，〓 ︻ 〓 ０﹁ ＾ 尽計ごｏ ｏ ﹁ ■９ｏ■■あど，ｏ ● ∽‘Ｒｃ一 ，お０■︻ｒ，´ ３一 Ｆ● ● ｏ ６● ３●∽ 一ｏ ５， ｏ ド︻ ｏ ｏ ａｏ● ｏＲ〓ｃ く ｏ ●，‘ ０●こ〓ｏＬるｏ や↓， ９〓¨ ョ もｏ 75 ０＞ ﹁ｍ↓く ０ ﹁ ●０ ↓ ●●■ ００ 〓 ヽ０ ２ ｍ ２﹁● SAFETγ OF PCT PLT COMPONEN'S TABLE 2. Pallent 6xposur6 lo sludy PLT Nu"ber of pat● nts N u n b e o′1 9 1 u d v ui ● ro a口 sn s ′ e n d p r O p o r t ( %o )。 Rece ved al,● ast on● ludy tranず ● uslon 651 11∞ ) R●● ●,ved O,Iy,lran,“ s10n 271(416) R●● ●lved more than l trahstusioぃ From 2 to 10ヤ ansfuJons 271(41o). From ll to 20 trans:usonS `77.2) From 21 to 40 trans,sbnS 33 15 1) From 4イlo 60 transfusOns ll(17) Fron 61 t● 80 translusbns 3(12) From 81 lo 100 tra“ l● 91ぃ ´ 7● 1) M o ゎ! h a 出 00 173nguSbns 3 0 51 Number ol ilansfuslons per patlont Mlan t SD 78± 16:2 Range ,156 Modian 2 IABLE 3, Adverss evants rslated to PLT trangfuslong classltled a5 traretslon reactlonsr ovent(olぃ`● ●￨。b9oNatbn) Nomber。 Ch‖Is Fever u“icatta pysPr..a 101わ oⅢl■3peC“ 19d) Skin rash(n。 Naus●a/vonhln9 訥評m uisg“´i HypotensiOn events reponed thatwere excluded as related to the Emsfusion (Table4), and 2 of these transfusions had serious adverse events reported that wete excluded as related to the transfusion. On aper-patient basis,42palients (6.5%)experienced adverse events after study'uansfusions. Eight patienG (1.2%) experienced adverse events after two differcnt study transfusions, md I patient (0.15%) had adverse events after six,difrerent study tEnsfusions, Among the patients experiencing adrerse events aftir transfusion, 32 patients (4.990)experienced adverse events attributed to the study PLf transfusion (possibly related, probably related, or related) and were classified as patients with a transfusion reaction. Thrce of the 42 patients had sedous adverseeventsafter PtI trarsfrEion, but for only I patient w6 the seridus adverseevent attributed to the PLI $ans. fusion. Of rhe 42 transfusion reactions in 32 padents, 33 transfusions were associated with a single symptdm ind/or sign, I with two, md l.with six Anong these 42 transfusiors classified as resulting in tansfusion reac,tions; the time to the first reactjon was valiable (Table5). Only 4 tEnsfusions were preceded by medication to reduce potential trilsfusion reactions (antihistamines and corticosteroids for 3 and corticosteroids alone for I transfusion). Translusions assoclated wlth suspected bacterial sepsis Five tansfusions were associatedwifi chills md filer or h!?otension that met institutiona] criteria for suspicion of uansfu sion-associated sepsis, resulting in bacterial cultures of PLlI components and patients (Table 6). Twentyone other PLI components were cu.lturedbased on blood center survei.llancepractice, but were not associatedwith suspectedsepsis,and a.Llof these were steiile. TABLE 4, Advers€ evenls classltled as unrelalod to PLT trsn€tuslons 01-010 01‐ 008 01つ96 01・ 099 Oヽ■68 01Ю98 01・ 106 01‐ 170 200 01・ 01‐ 389 421 01・ 427 01・ 395 01・ Adve66 evenls' Faw, chllls, nausoa, vomlting transtusions ritstreaclion betorE }liu"l""l",l"=15 TABLE & iranstusiona assoclated wiih 'susDocledbact€rial seosis Palent,D Ⅵ lai s10ns Cunure resun 01‐ 007 36:W38ぴ C Pa30nt blood oullre no9auv● 8P・150/80 ve ure nega‖ 0'ヽ 039 3al´ 61°C Paヽ ont bbod cu“ SP 140/80 464 Afebい ro PC culuro noga,ve に,seぃ 01・ hypo、 9nsion . 178 39,C12 hr arler Pc cu"ure n9ganv. 01‐ 8P120/80 098 _370/39 9C PC neg。 01・ “ ぃ .dentJ abs,oss i BP 60/40 ' 8P = blood pfossure; PC = plalelBl Componont. ′ovents(%) 14(186) 14(186) ●( 5 3 ) 4(5,3) 3(4o) 0(40) 3(40, 3140) Adve€e ov€nls (n = 75) rgporlad Bfler PLT translusionsattrib. ul€d to th9 trssfusion and classifi9das par{ of a lransfusion reaclion hvolvlng 42 of 5l06 lransfusions. Paient Serious advergs events afier PLT transfusion TABLE 5. Numbgt gl ttudy translusions betoro th€ flret transtuslon reaction １２３４５田綬爛 of adwrse events associated with Eansfusion reactions (Table3). One of 42 (rmsfusions was reported with a serlous adverse event, Grade 3, causally related to PLf transfusion. Nl of the other tnnsfusion-related adverse events were Grade l. Thirteen Uansfusions had adverse OSSELAER ET AL. Causlityt Probably unrolated Ca「 dほC arrhythnl● tod Probably un7oは PrObably unrolated HypOtenい on Chms PrObably un子 Olated Ch‖ 3,headache Probably unrela● d 疇 V01o'“S,い ソp●enSOn,ooSIわo υ areはed ,7● 0yspn“ .●a,Sea,v●“￨"ng baЫy unreは led Fev● `oわ‖s PrObably unrelatod Chms prObably unrelated Chms,nau9oa,vom聞 ng Pr● bably unielaled Fever,oyspぃ ea.chost‐ abdomitt pan PrObabv unrelated Chms Probaoly unrelated Chms l unに ●t“ Grad€t 1 Basis for causaiity assesment Prior intoctionuider treatment Condltionbefore iransfusian Hypoienslonbefore i€nsfusion Anxiety cfEis, not v€dtiod as chilig, Do fover F9v€f betore lransfusionwith Dior Infoction Pdor sepsis dua io dehtal abscesss Indwellingcatheter infoctiondocumsnted Febdle nBulropeniabefofe transfusion Ev6nt sfier RBC transtusion Coincid€ntwith other medications Os€t 2 hr Eft6r iBnstugid, blood cultures negative O6€t 76 mln after lansruslon, blood N,lures negalive No t€vgr incr4$, PLT unll culturo regative AdveEe ev6nt5 repodgd aftgr PLT transfusion. t CaBd relalion to trssluslon a9 assessed by pdmary care physlcian. t AdveBe ev6nl svgrity grade whgfer GBd€ 0 = lsolatEd dygfwclion wilh@t cl;nicald biologi€l manitoslation;Gradg 1 = absence of lmmodiato gr long-lem llfa.threateningconsequsn€; Gr€de 2 = long-lem lire-lhteatening@nsequon@; Grade 3 = lmmediate lifelhreatenlng @nsqq€n€i Grado 4 e d€alh. Volun●48,June 2008 TRANSFuSiON loo7 Patient 01-007 had chills; fevet and ur(icaria after a transfusion. Culture of a tubing segment was positive for micrococms, but blood cultue ftom the patient was negative. The utimria was attdbuted to antibiotic medication, The tubing segment clrtwe rcSult was considered a laboratory contaminant. P€tient 01"039 exped" enced chiLls without fever, but with dyspnea after a umsfusion. No other slmptoms or signs were reported. Culture of the administration tubing set was positive for coagulase-negativestaphylocgccus, but blood cultues from the patient were negative. Patient0l-464 experienced posltlansfusion hypotension. Culture of a detached tubing segment was positive for Smphylococcus warneri, bul cultu€ of the .PLT component and blood cr:ltures were negalive. Patient0l-178 developed fever and chills after a P.II Eansfusion with a positive blood culturc for Escherichlacoli. culture of the PLT component, howeverr was nsgative. Patlent0l-098 developed fever (39.9"C)with chills and hypotension l2 hours after a PLT transfusion. Blood culture was posltive for lhe presence bf Actinornyces,but qultue of the associated PLT component was negative; Subsequently,the source of sepsiswas idertiffed as a dental abscess.In summary, no posttansfusion adverse ev€nts suspicious for tmnsfusion-associaied sepsis were cohfumed witi c-oncomitant-positivePLI component and patient blood cultutes. 1068 TRANSFUSIONVolume48, June2008. Three serious adverse events were reported after PLT uansfusion. Patjent0l-096 had severe hemodynamic instability after liver biopsy associatedwith bleeding and was tImsferred to intensire care.After the onset of hem- . orrhage, she received a study PLI timsfusion followed by severe hypotension (blood pressure, 4212?j hean :nte, 92 beats/min). She was treated with fresh-frozen plasma (FFP), vasopressors,and fibrinogen and recovered. The primary care physician assessedfte event as probably uroelated to the PLf [ansfusion and aftributed the hypotension secondary . to hepatic hemorrhage wi& hemodtramic instabi.liry Patient0l-098, recelving chemotherapy for acute Ieukemia, experienced f*er. chills, and hypotension l2 hours after his 3lst PLI transfuslon. Subsequent blood cultures were pirsitive for the pr€senccotActinor(yces,but the PLI component culture was negatiw. The source of sepsiswas attributed to a dental abscessand was classified as uruelated to the PLI oansfusion, Patie;t 0l-464 developed hemorrhilge during mitral va.lvesurgery ud was treated with PtT transfusions and methylene blue FFP He expeiiencedhypotension afterthe second study transfusion. Cultures of the PLT component and blirod culturcs were negative. On6 day later the patient experienced a second hypotension episode after' bansfusion of red blotrd cells (RBCs).The investtgator\g attributed the event a6 an allergic adverseevent related iol\ the PLI tnnsfusion. The pati€nt had no other allergic slmptoms. The patient recoveredand was discharged in good condidon. Risk tactors associated wlth tranEfuslon reactlons Both patient and PUL componenl characteristics were analyzed for association with tmnsfusion reactions, The analysesshowed that 6.0 percent ofmale patients expedenced at least one transfusion reactioh and 7.3 percent df the female patients experienced.at least one transfusion reaction (p = 0.59; odds ratio lORl, I.I9). Stratification by age showed tbat 4.6 percent of the patiants older than 64years qf agq presented with at least one lrmsfusion reaction compared to 8.3 percent of patients b€low 64 yea$ of age (p = 0.06; oR, 0.5a). Flnally, 8.8 Fercent of patients with a prior history oftransfuslon experienced at Ieast one reaction while only 4.5 percent of patients with no prior transfusion hjstory experienced at least one reaction (p = 0.07;OR, 1.99).Thesefactors may be confounded with the diagnostic category of the patients; however, there were no signncant associadonsbetlveen diagnostlc category and tahsfusion reactions. Most of the transfusions with attributed reactions were associated with apheresis preparauons. Only one random-donor PLT component Ms reported with a Eansfusion reaction, but this low incidence of reactionswab most likely due to the SAFETY OF PCT PLT COMPoNENTS disproportionate use of apheresis components in this study and not a true effect ofprepalation method. Extenl ot exposure belore the tlrst transtusion reaction Among the 42 tEnsfusions associatedwith a transfusion reaction, rcadions occurred after single and mtrltiple tranifusions (Table 5). These data suggest that repeated exposure to INTERCEPTPLfs did not increase the likelihood of a transfusion reaction. Arnong the 10 patients without a previoustransfusion history who experienced a transfusion reaction, 3 patients had an event at the fust PIT tmnsfusion, I after the 4th, and 6 patients after more thm 5 transfusions. Patient 01-l13 experienced the fust reaction (unicalia and flushing) after the l39th INTERCEPT transfusion. Thus, for this patient population without prior blood product exposure,the fisk of a $ansfusion reaction after INTERCEPTPLIs did not appear to incredsewith increased exposue. DlSCUSSION Generally when a new type oflabile blood component is introduced Lrto routine clinical practice, initial information cbaracterizing the safety profile is derived from a limited number of obsewations during the clinical development phase,3The intfoduction ofPCT PLTSinto loutine clinical practice provided an opponunity to collect more information on the tolerability and safery ofPCTPLTSin a broader patient popdation and under routine clinical conditioru in contEst to a clinical tdal enyiroment. This approach is consistent with the recent recommendation flom a consnsus conference lhat new blood safety tecbnologies should be evaluated with postmarketing hemovigilancestudies.ro. A prospective observational study with obl.igatory reporting for all uansfusions regardless of outcome ws designed to assesEthe safetyprofile ofPCT PLTsin routine clinica.l practice, The data from the present study represent the largest prcspective experience to date for record. ing potential adverse events associated with PLT transfusions compared to.prior studies of rctrospective design and limited size.rr'raThis study was planned.to be consistent with European hemovigilance pracdces in which reponing of all grades of transfusion.associated reactlons has been emphasized.s6 [n contrast to passive hemovigilance studies, in this study obligatory reporting for all PLT trilsfusions was required irrespective of outcome. This study focused on adverse eventslhat could be linked to PLT transfusions, specifically in the first 24 hours bfter transfusion, but there were no specific llmitations on when adverse events cou.ld be reported afrer uansfusion, Thls study captured information on rcpeated (ransfusions withln patients to determinepoten- tial effeits of repeated exposure to this new q4re of PLT component. . A potential limitation ofthis studywas the absenceof a concutent contlol group receivlng conventional PLI components wlth which to determjne a comparative incidence of acute tBnsfusion reactions..Arother limitation was the polential for overreporting due to the absenceof a blinded design and the increased awareness among obseryers that a new type of PLI component was under evaluation. Thesepotential limitations were addressedln several ways. A large portion of the trmsfusions were administered at the Mont Godime Blood Transfusion Center which had prcspectively collected data for both PLI and RBC transfusions during an l8-month period before routine implementation of PLt components rreated with pathogen inactivation. After the uriiversal introduction of $eated PLI components into clinical use atthis center,the methods for RBCsdid not change. During both periods of observation, PLI ASs were ued to reduce exposure to alJogeneicplasma.rsThus, in this centet we were able to compare the prevalenceoftransfusion assbciatedadverse events with the sme group of obsewers for one component with a new intervention (PCT PLTS)md another componentthat wasunchanged(RBCs),Basedon a com' peison of the two observation periods, Osselaer and coworkerersreported a significant reduction in rbactions to treated PLf components, from 1.3 to 0.9 percent (p = 0.02), while the incidence of reactions to RBCSwas equal in both periods {0.4%). The experjence from this two-period, two-componenr analysis suggested that obseryer sensitivjty for overrepoitjng did not gccur In addition, these data prwided a background rate for acute uansfusion reactions for leukoreduced PLf components with PLTAS(I.3% of trmstusions). Other estimates on the background prevalence of transfusion reactions can be obtained from the litentue. On a per-transfusion basis, the prevalence has been reported to nnge from 18 to 3l perent; however, tlese studies were conducted some yeils ago with variable methods ofPLT preparation,rr'r6'rB More recendy,the incidence of moderate md severe transfusion reactions has been reported from the TRAPstudi which examined 8769 PLf transfusionsin 598 patients during induction therapy for acute leukemia.reThe overalj lncidence of reacrions was 2.2 percent of tilsfusions, md 22 percent of patients experienced at least one transfusion reaction. In comparison to the TRAPtdal, in this study in wNch all grades of reactions were reported, both the proportion of transfusions associated with a reaction {0.890)and the propoftion of. patients t4.99o) dperiencing at least one transfusion reacuon causally attributed to a PLT component were lower Another comparison can be made with data from the hemovigi.lancenetwork in France.5In that study, which ヽ ′ 01● ne 43.」uno 2008 7RANSFuS10N 1009 OSSELAER ET AL. reported data for transfsion reactions during 2 years in which the leportipg system was fust implemented, an incidence of four eventsper iOO0PLTcomponents (0.4%) was reported. This may be an underestimate, howevet since each whole-blood PLI concentrate in a pool was tabu.lated as an individual component. More recently, Kerkhofis and colleaguesla compared the incidence of uansfusion reactions for leu-koreducedpooled PLT com. ponents in plasma and plasma with AS in a study of 168 patients and 765.transfusions. They observed an incidence of.5.5 percent of transfusions with reactions for PLTsin plama versus 2.4 percent of transfusions for PLTs in a mixture of plasha and AS. On a per-patient basis, 9.5 percentofpadents transfusedwith PLTsin plasma-ASs had reactions compared to 15.5percent of patients supported with PLTssuspendedin plasma In this study, which is the largesr prospective PLI transfusion srudy to date specifica.llydesig{led td caprue all gradesofuamfusloh reactions,tre prevalence ofreactions per timsfusion and per patient was at the lower rmge of those reported in studieswith conventional com, ponents.Youngerpatlent ageand prior expsure to blood transfusions were risk factors trending to a higher incidence of Eilsfusion reactions. Recently,a higher rate of transfusion reactibns also was reported in a hemovigilance suwey of pediatdc hematology patients.20 Prior dposure to INTERCEPTPLT trmsfusions did not inffease the likelihood of a trmsfusion leaction. In comparison to. other studies of PLI components in plasma-As mixtirres, the incidence of transfusion reactions on a per.patientbasis forcomponents preparcd with PCTwas reduced funher. lmportantly, this study eruolled a substantial number of patients with hematologyoncology disorders treated with complex therapies and suppqned with rcpeated PLf transfusions as well as swgical padents requting PLI support. No incidents of TRALI, tEnsfusion-uansmitted bacterial sepsis, or death associatedwith acutetmnsfusion reactionswere obseived in this study. B*ed on this experiencein a broad patient population, PLI components prepued with PCTwere well tolented in routine cltrical practice.The types and severity of acutri reactions to PLI components preparcd with palhogen inactivation keatment were consistent with previous reports of adverse events to.conventional PLI components, md the data from rhis study provide addi. tiona.ldata on the saJetyof PUf components ueated with amorosalenand IIVA lighr. ACKNOWLEDGMENTS The Dataand SafetyMonitoringBoardwascomposedof the fol' lowingmembers:Dr Hiley KleiD,Divisionof Trusfusion Medicine,Natlonaltnstituts of Health,Beth6da,MD; Dr PaulNess, ltanstusionMedicileDivisioD;The lohnEHopkiirsHospiral,Bal. timore,MD; Dr lacqueeCinqualb_re, CHU de Hautepien€,Strast070 TRANSFUSION 48,Jun62OOg Volume boug, Frucel Dr Miguel Lozuo, Hemotherapy ud Hospita.l Clinic Provincial, Hemostasis, Barcelona, Spain; DtDantele Sondag, Sewice Francophone du Sant, Brussels, Belgium; DrPaul Strenge$, Intemationa.l Society fot Blood Trusfusion, AjnEterdam, Netherleds;and ri6, Aheli€n Red Crss, Dr Roge! Dodd, Hollud Rockville, Laborato. MD. The authors DrAntonio Iacone. CentroTl6fuslonale, thank Ospeda.ledi Pescaa, for reviewing the manuscripl REFERENCES I. van Rhenen DI, Gullikgson H, C@nave IP, Pampfulon D, Ljugman P, Klut€r H, Vermei) H, Kappers-Ioume M, de GreefG, Laforet M, Lioure B, Davis K, Marblie S, Mayaudon V, Flment L Conlan M, Lln L, Metzel P, Buchholz.D, : Corash L; eUToSPRITEtrial. Tlansfusion ofpooled buffy coat platelet components prepared with photochemical pathogen lnacrihtion rreatmenr: the euToSPRITEtrial, Blood 2003i101:2426-33. 2. Mccrrlough ,, Vesole DH, Beniamjn RJ, Slichte! SL Pineda A, Snyde! E, Stadtmaue! EA, Lopez-Ple I, Coutie S, SFauss RG, GoodDough II, Frideyrl. Raife ! Cable R, Murphy S, Howard F 4th, Davis K, Ltr IS, Merel P, Corash L Koutsoukos A Lin L Buchholz DH, Conlan MG, Thera- . peutic emcacy ild saJety of platelets beated with a photochenical process for pahogen inacuvationt the SPRIM t> tri8l. Blood 2004;104:1534-41. 3. Snyde! E, Mccuuough L siichter St, Strauss RG, Lopez-PlzfI, Un l-S, Corash I" Conlan MG for the SPRIM Study Group. Clinica.l safety df platelets pho tochemically teated . with motosalen HCI udultravioletA 4, Sllchter St, Davi6 K Enright H, Bralne H; Gernsheiner T, lightfof pathogen lnactivatlon: theSPRlNT trial. Tlansfusion 2005;45:18il-75. Kab K,, Kickle! T, Lee E, McFarland L Mccullough t, Rodey c, Schiffer C, woodson R. Factors affectihg posttransfuslon platelet increments, platelet reftactoriness, od platelet traNfuion interyals in thrombocytopenic patients.Blood 2005;105:4 106-14. 5. Andreu G, Morel P, Folestiei F, Rebibo D, tanvier G, Hewe P. Hemovlgilance neftork in France: orguiation and ana.lyslsof immediat€ trusfusioq incident reports from 1994 to 1998. tanstusion 6. 2002;42:1356-64. Faber rC. Haemovigilance'in Europe: now and tomorrry. Ini Rouger Pi Hossenlopp C, editors. Blood transfusion in Euope. Paris: Elwvjer SAS;2005. p, 2t3-32, 7. Ware L, Matthay M. The acute respiratory distress slndrome. N Engl I Med 2000;342;1334-49. 8. ,anerzkoK, Cuenave IP, Iouter H, Kientz D, Michel M, Beris P, Lioure B, Hastka I: Marblle S, Mayaudon Y Lin I., Lin IS, Conlu MG, Flment t. Therapeutic efncacy ed safety of phorochemically treat€d apheresis platelets pro. cessed with il optimiad integlated set. Trusfusio! 2OO5; 45:1443-52. 9. Glass tA, Wafa T, Rems A, Wages D, Corash L, Ferrua. lL, Lin L. Prev€ntion of tnnsfu slon-associated saJt-versus- SAFETYOF PCT PLTCOMPONENTS host disease by photochemical trearment. Blood t999;93: 3140.7. stored in platelet additive solurion ll versus plasma, Blood 2006;108:3210-5. Klein HC, Anderson D, Bemardl MJ, Cable R, Carey W Hoch lS, Robitaile N, Siviloni ML Smaill F. pathogen inactivation: making decisioN about new technologies- Osselaer tC, Doyen C, Messe N, Vo Hooydonk M, Jacquet M, Sonnet A, BoslyA, Flament I, Corash L, Routlne us€ of pEliminuy platelet cohponents prepaled with photochemical treatment (INTERCEPI platelets)r impact on clinical outcomes Chmbers't and resouces, Blood 2005;I06:129a. 'Heddle NM, Ka.lma L, Singer r, Richalds C, Fedak p, Walker I, Kelton tG. The role ofplasma flom plateler concentmtes rcpofi of a @nsensus conterence. Vox Sane 2OO7i93tl79:82. A, Ktuskall MS, Pacini Dc, Donovan LM, Febrile ractions afrer platelet trosfusion: the effect of slngle w!$us multiple doDors. TtaDsfusion 1990;30:219-21. dewildt-Eggen l, Nauta S, Schdjver IG, Kooy MvM, Bins M, Bn ProoiFn HC. R€ctions and platelet incremeDls after tEnsfusion ofplatelet conceDtrates in plasma or an additive plution: a prospective, randomized study. Tlugfusion 2000;40:398.403. Heddte NM, Blaichmu ln, Sher GD, Constetini I4A, Meye! RM, Lipton IH, Walke! Il, Patterson B, Roberts RS, Thorye KE, Lwine MN. A ratrdomized controlled trial compaling r}te frequency of acute reaciions to plasmaremoved platelets and pre-stolage WBC-reduced platelets. Tlansfu sioD 2002;42:556-66. in tansfusion reactions. N Engl J Med 1994;331;625-0. MM, Ch@bers IA, Kluskall MS. Limired emcacy of leukopod platelets for prcvention off€blile tBlsfusion Muguo reactiors. AD I Clin Pathol l99l;95:733.8. Heddle NM, Klma IN, Grimth L Roberts R, Shukla C, Kelton J6. A prospectiw study to iij€ntify risk factors associated wilh acure reactions to platelet and red cell trdsfu1993;33:794-7, sions, Tiustusion EniiSht H. Factors influencing nioderate to severe reactions to PLI transfusions: exp€dence of the TRAP muhicenter clinical rrial, Trssfu sion 2003;43:I545-S2. Kerkhofs tH, E&enboom JC, Schipperus MS, En Wordragen-Vlaswi*el Rr, Brod R, Hfley MS, de Vries Argelini.Tibert MF, Curde C, Slaedts M, Corash LM, Rasongles P. Safety ofpla(elet componenb prepaEd wi& photochemical treatment (INTERCEPT) tran6fused to nR, Bdge R, En Rhenen Di, BEnd A. A muricrDte! randomjred study of tbe eficacy of tresfusions with platelets pediatdc oncolo gy-hemarology patienrs, T!ansfu sion 2007;43(S3):224. lt ∞ト Volumo 48,」 uno 2008 TRANSFuS!ON 11071 販後調 査及 び観察研究の報 3'6 1 C Oselaera,αl サ oumJ cOml翻 18器 膳期￨&]拙 湯 :蠍 鶴♀ programme An activehaemovigilance characterizing the safety profileof 7437platelettransfusions prepared with amotosalen photochemical treatment J. C. Osselaer,rJ. P. Cazenave.2M. Lambermont,3 O. Garraud,'M, Hidajat,s L. Barbolla,6R, Tardivel,t L, Defoin,r C. Wallcr,2 L Mendel: J, P, Raidqt ? G, Kardel,2 R, De Meuter,r p. Fabrigli,. D, Dehenau,s J. L. Arroyo,6 F, padr6n,6 H. Gouezec,T M. Corral,s M. Jacquet,e D. sundin,e L Line €t L Corashe lSlooiihontfuion Cente,CliniqusL)nivetsitohsde MontGodilne,lJnift$itt Cothotique de touvojn,ywiLgalgjun 2tR Atsoce, Ftunce St.asboutg, lsetuia du Song, gelgionfedC.osrfros( U.iwGity Hosp,to,, 8/ussers. BcJg;um ' Au@ryneLoir( st. Et'c4nqFronce EFS sElood Trunsfuiaa. AZ St JsnAV, Btugge,Belgium 'C.nto de Hemate@pio yHcmodon;n dc Costt,o y L.on,vottodaild,spoin 'ff5 Iretoqne,ReoncsFronce sHosp{tai Unl46itor;o dr Sotomoh@,Sotononco. SDoi n 'gCerus Corporotiotr,Corcod, CA,U5,4 V(,(5,t臓匂ぃiliみ Methods The focus of this ongoing haemovigllanceprogramme is to dooment all AEs asociat€d with PCT-PLItransfusion.Data collectedforA_Esiiclude: tine ofevent aftet starting transfusion,clinical descriptions,i/ital signs, rsults frorn radiographs and bacterial cultures,went sderity (Grade0-4) and causalrelationshipto pCT-PLT tmnsfusion. ResultsOne thousandfour hundred_ parients(nean 60years, range l-96) received PCI-PLI tnnsfusions.The majodty of the patients(53.40lo) had haematolos/ioncoloA/ diseass and requiredconventionalchemotlerapy(44.8%)or stem-celJ traniplantation (8 6%). Sixty'eight PCT-PLTtnnsfusions were associatedwith AI. Acute tnnsfusion reactions (ATR),classifredas an AE possiblyrelated,probably related;or relatedto PCT-PLTtransfusionswere infrequent (r = 55, 55/.743?= 0.706)and most were of Grade t sweriry. Thirty-nine patients(39/1400= 2.8%)experi€nctdone or moreATRS. The most frequently reportedsignslsymptomswere chil)s, fever,urticaria,dyspnoea, nausea end vomiting. Five Als were consideredsevere (l Gnde 2); however,no causalrelatidnshipto PCT-PLTtransfusion was found. Repeatedqposure to pCI-pLI did rot increasethe iikelihood olan Afi. No casa oftransfusion-relatedacutelung injury and no deathsdue to PCT-PLT transfusions were reported. Betived: 25 Octobet2CA7, td isEd24 Dtcr hbc, 2007, rccepted24 Decenb.( 2007, publishedonIine 30 ) onuory 2Ng ConclusionsRoutinetansfusion ofPCI-PLT is well-toleratedin a wide ranqe of patients.ATRSrelatedto PCT-PLT transfusionwereinfrequentand mostwercof;ild sweriry. Key words: PCT,platelets,haemovigiJance, safefy,INTERCEPT. Correspoadflc(LilyLin,Cr(usCorporation, 2411StanwellDrive,Concord, CA94520,USA lIn@cc(utcom E-marl: Materials and methods @20oSThr Authods) prblishingLtd.,uot songuinisffi;;;, ;l;::, Joumafconpilation o zrjogBtackweil ０ト Background An activ€ haemovigilance prognmme was implemented to suryey adversewens {A.E)associatedwith transfusionof platelets photocheinjcaltyheated with amotosa)enand ultraviolet A (PCT-PLT). The results of 5106transfusionshave already been reported.Here we report the results of an additional 243? pCI-pLT transfusions, Introduction INIERCEPT BloodS,srenwusesa phorochenical rreatnenl General shrdy design nethodology [PCT: amotosalenplus ultraviolet A fitvA) Iightlto inactjvate virus€s, protozoa, bacteria, andleucocl.tes This was a prospecliveobseruationalactivehaemovigilance in plalelet [PLT)and plasna components.The PLT system study.The objectiveof this study was to documentthe receivedCEMark registntion in Europein 2002.Several transfusion safetyprofrlefor approximarely 7500pCT-pLT centresin Bellium, Spain,Nomay and Italy b€ganroutine componentspreparedwith the INTERCEPT Blood Systemil productiof,of FCT-PLTin 2003.An activ€ haemovigilance for platelets(CerusEuropeBV, Leusden,the N€theilands). programmewas imnediatelyimplementedto prospectively Thesecomponents wereprepared in thrercentres ir Belgjum collectinformationon PCT-PLT transfusions administered (CTSUCL Mont Godinne,CTSDrabant-Hainaut and AZ patients to ln routjnectinicalsetlings.Prior to CEMark Sint JaD AV), three cenBesin Fmnce (EFS-Alsace. EFSregistration,the safety data of PCT-PUIwere primailly Auvergne-Loire andEFS-Bretagne), andonecentrein Spain 'obtalnedfrom controlledclinicaltrials with a limitednumber {CHEMCfLValladoiid)and admlnistered to thrombocytopenic ofpatientsand pr€determined clinica)and safetycnd-points patientsunderstandardclinicalpmcticeiir hospitals. There [l-3], The postmarketinghaemovigilanceproglammeprowereno randomization requirements, no inclusionctlteria videda neam.td eliend the characteizarion of the safery abd no exclusioncriteriaoi patientsotherthar the need profileofPCT-Plf in routineuse and in a broadpatient to receivea platrlct transfusion, Baselinedemographical populatiotr. Thercsultsofth€ fi6t 5 106PCI-PLTtnnsfusions infomation was collectedon all studypanicipanis.Patjents have alriady beenrepoited[4]. With additionalcentrcsin wo€ assigneda centre-specifKstudy numberto prcserye Belgim, SpainaildFrance stating withthe routineproduction anonymity. ofPCT-PLT, the database ofthis haemovigilance piogramme Patientswho Keiwd bansfusioroof PCT-PLT weremonihasbren expanded{51. toredfor any Als afterthe start ofeach platelettransfusion, In March 2oF, the CanadianBlood Servicesand Himawhjch is consistentwith EurcpeanHaemovigilance Network o€anizeda consensus Quebec conference to providerccom- Komdendatiotrs for suNeillanceof AE to transfusionof mendatjons andguidedecision-making aboutnewiathogen labilebloodcomponents, and with thoseof nationaltransinactivationtecbnotogi$ [5]. The panel, consistsof nine fusion services[7,8].However,in this study,repoftingwas healthcare profssionalsand membersofthe public,slressed obligatoryfor all PCT-PLT tnnsfusionsiD eachparticipating the iEiportanccof postmarketing suweillancestudiesin the clinical site.A transfusionRport was rcquiredfor eachpLT introductionofnew technologies for blood sfety. Thepanet transfusiontegardlessofwhether or not an AE occurred,In reconmended that specifrc studiesshouldbe mandated by caseof ocorrenceof ari AE.additionalclinicalandbiological the reglrlatory authodtiesandsupportedby thc nanufactureF informationwaScollectedto allow diagnosisard assessment and/or the blood suppliers.Postmarketingsurueillancefor ofcausality and severity.The data in the final database adverse/eactionsto pathogeninactivationproductgshould werc anonynousand were reportedon a per-transfusjon belinkedto the mtional haemovigilancts)6temsif possible. baslsaswell ason a per-patientbasis.Tnnsfi.tsions associated Depending on the new pathogeninactivationtechnologjes with seriousAEs were reportedJn great€rdetail, implinented,specificadditionalsuryeillanceoutcomes nay be identifiad,Thepanelalsosuggestedthat Chronjcally Study repon forms tnnsfusedpatientsmight.serveas an ideal surveillance populationto identjfylong-termtoxicjtiesofpathogenThe Rpon fom used for this haemovigilanceprograilme inactivatedproducts, wasdwelopedon rhebasisof haemovigilance Rpon form The actjvehamovigilanceprogrammedescribedin this alreadyin use,Information wis collectedin sevenl broad study is in concordanceuith thse recommendations, categoric:patientdemogruphic/diagnosis dara,plateletcomAhhoughthis prcgnmme is not directlylinked to a specifrc ionant characteistics. tnnsfu sionryentsanddosm€ntation countryhiiemovigilance systemnor designedto replaceany of all AIs followtngtrasfusion.An aate tnnsfusionreaction existinghaemovigilance system,the fomat of data collec(ATR)wasdefrnedasan AE po$ibly relared,probab)yrelated, tion is modelledaftilthedata collectionformatofthe French or Rlatedto a PCT-PLT tnnsfusion. haenovigilancesysten for documentationof transfusion AEsweregrudedfor clinicalseverirywilhin rhe foilowing incidenb[7J,Thefocusof the cuBentprogramme is on a]l categories:Gmde0, isolateddysfunctionwithout cijnical or advere events(AE),seriousot non-serious,ocruring after biologicalnanifestation;Gmde l, absenceoflmmddiateor the startofPCT-PLTtnnsfusion. Followjngthe recentreport long-termlife-thrcateningeffects:GrudeZ, long-tem lifeof 5106PCT-PLT tnnsfusions[e],herewe reponthe results threatening effects; Grade 3, immediate life-threatening ofan additional 7437transfusions ofPCT-PLT. effmbi andqnde 4, deati. Foreachtransfrsion,the following 資”●´ ∽ 一 こ●２ 一 ｏョ∽ ，コ０ 一一ｏ２い０ ぅ一 一 ■ｏヽ ヽョ一＾ ｏヨ“ ｎ ヽｓＯヽ お， かくｏ つξ 〓０ 一 メ ｎ〓Ｆ ・８■一 ，● ミ手ヽ アヨ¨ ， ゴマ ｏ， ●２３ 一 一 〓 ＾ つい Ｆａｏ ユ，弁ヨ Ы∽ す・ 簾ョＰσ８●・ ， ﹂ 営 ，ａｎ・ ﹁ニヨｏ●ｏ● ｏ″ ﹂ ヨ・０ヽ´ のす０∽ ´ ョ” ，８６更 ９，お∽ ｏ ｏｏ ﹁ヨｏｏＰ ８∽ ´ ョ，‘∽ Ｐ くｏヨ一 ざ‘ｏ”すｏｏ ズｏＬＦ ｏすｏ ５ｏｏ● ４ ｏ２Ｆ ●げ０●ヨヨ ２ ｏ３， 一●。一 ＞ｕ ，■ つ０３●いいｏｏＬＯσｏのス會ｏ Ｏ， ヽ ０一 ∽﹃ お０オｘ´〓２ｃ，●” どＬｏ３ ヽ０﹂ ●● ど一 ｄ，■２●８一 ａき ，ｏユ員‘い０ ■２●２ ●ヽ〓一 ヨ∽ Ｘ ●ｌ ｃ凛 ｉ ｃ颯 Ｊ ｏ壁 一 １ 一 員 一 笠 ヽＳ ¨ Я 一ヨ ３ こ ¨５一 斎 澪 ” ３ ｏ■ ａ Ｏ●∂ ■ ，コＱ ｏ﹁年 ３ ●Ｆ ＾ ３ コ“ご 一８ １ おヨＲ ヽ〓昴 げσｏ﹂ ｏお参‘澪 ●５０ す０，■ ●″・＞σヨ？ピ ユ う一 一 ■８ Ｅ ●σｏ３ ８ ２ く”〓 θ ■ ０ 二 ● Ｒ ３ 一餃●３ ´ ″ 一８ ９ ０‘澪 ∽︵ わ〓０ 一Ｘ■，■ ●５ａ ピｏ２ｏ” ご一 ″ヨ＾ ＾ ‘” ，コ０ 〇一 ｏｏ ﹁０ヨ ０，´ ｏＯａ う０ヨ一●うｏ●＾ ´ｃ一 ●８ お， ‘０お お８ ａ ａ 〓汀 ヨ〓∽ Ｒ ｒ ａ ｉ ３ 〓 ＞ｍ♂ ぎ 〓一 語 ↓ヽき︻一 ””︹ 記ｕ一ど，ｏ， い ﹁﹃ ´ Ｃｏ ０ ＾ ″ Ｏ﹁︼ ︵ｎ 一０ ０ Ｈ 口ｏ ” ｅヨ﹁ｏ り ﹁， ●” ，Ｆ２２ ｏ 一 ０く ”ｏすｏ ｏ日りｏ３０コ● 〓０ み ｏ”゛ｏヨ お ０３″禽● お∽ そａ ｇコ ︲ ュｏ ａ ｌ ， ，の ■すｏ一 ・三ｏＯ一‘ ８ ■ ８ｎ ｏ の０ュ 凛 ｔ Ｓ ３ 一‘ス， く２‘■ｏ ∽資”，αヽ０ ２潟３こぅ” ０一 ｏっ ｎ，ュお． ｏ ９ ０ｏｓｏ， 一 ヽ３一 〓●０一 ３” ■●一一 Ｐ，ｏコム” ■０お ●０お０３ｏ ＾ 庁０ ●う∽ ヨ一 ３ 品 ﹁？ ３ ，ユ ヽこ ８ ●ヽ ■ ，ｏ聡 ３ ●８ｏこ一 凛 ８ ８３ Ｒュお． ３ 社“ ｎ ●一¨ぉ一〓 ぅｏョ■●コ００■一 ２イ０ コ■●ヽＬ ら¨色“一 ざ３● ﹁ｏ ＞一 一８ ヨ一０●０コ● 〓０日 澪ｒｎＲゝ●” Ｑ‘ｏ ¨ 一 ｏ， ９，■ σ 日一 ０３ ヽ ■一 一 一””∽ｒ ●ｏ ン・ ＞●， 〓 ”ぎヨｏ 一 ｕ ，ｎ ■０＾ヽｐ﹂ｏ﹁”二 ｏ”一８う ｎｏ ， ｏ ′ 一， ・ ″‘ｎｏ，つヽ■ざヨ︵ ＞ヨイ‘一のｏ〓∽ｏｏ営営ｏ●”ｏ●，ユ・ｒ●の，髯ス・ ﹁” ∽ Ｌ ０ ■ ユ ” 諄 一 ，い０■ 〓”０ 千 ゛ ヨｏ●ｏ ｏ ∽‘ ● ヨｏ●ｎ ｎ ●●ｏＰ に ′ ´ ・ ● ｃ´多 コ●Ｅ 無 ８ 〓”９ ８ け ８ ●●一 望 ｏいＯｘ ６ ． Ｊ一 ド一 ●こ ８ ︺ 品 い・ ■ぉ﹁ 冶 増 ３ ａａ Ｆ 、﹁一８ こ 苺〓ｏそ ０いＳ や一 〓 〓ヽ ヽう０ いいま Ｆ おあ ２２ ■ ｏ●〓，こ ●■一 一月君 ａＱ●一 ３ ヽ日８９ Ｌ８ ＴｏヨＶＬ ∽︵ ″＾ 庁巴 営 Ｌヽｏｏ一 ”＾ ヨ８ ＾ｏ， ０かぐ 〓〓 多ｏマ ｏつｏ■ ｏ﹁ｏ﹁＞見 さ二 汗 ＾ 思〓 Ｐ∽¨ ｏ３ ． ０ヲ 〓０一 一 ︻ Ｓ， Ｐ一 ３ ｏ■ｏＯ﹁ 汀 ８ ォＯ ｏ８〓 ｏＲ ”３ も 呵 ︵ ●８ Ｑ 〓∂” ゴ● ヨ‘ヨげＲ ｏ﹁”ｎ７”ｒ↓ ●ｏ﹁一さ∽ ざｓ∽ σヽ 日舞δコ ｏ■ ＾ す０﹁ｏＬｏ●＾﹁０一Ｃ一 す０●〓ヽヽ 一０∽ｏつ ｏ●ｏ● ｏ８ ”一 ｏ一´ ”ｏ一 ﹁ｏＬＯコ＾︶´ ０■ｏ 争 ハ”う↓‘﹁Ｅ〓思 ３一ど総 ， ，う０´ コ●ｏゴ営 月 ″” 一 一 ′ 一 θ Ｏ﹁多 ｎ＞” さ一 一 ざ● Ａ ，〓 一ご∽ ●ミ ヽ”ヽ″″一 一■ ■９ ８ ，１ 一 ●●ｍ ●´ｏ一，コ，〓 ｍ ｏ”〓 ｐ一為 ＯｃＯ，ｏα´ ０お一ｏ■ ，〓 、”一ｏｏｏ‘﹃ ¨ｏ´ ６ ヽや ０３ じ 留 〓 汀 澪〓 一 ３ 一〓甘 Ｒ ３ ３ ＞， ３ ， Ｃ 澪 のａ ｔ 〓喩一 ″ａ″¨＾ さ一 ざ，■● ０げ 壽● ● らヽ ● に、ｏ 毬ａ∽ い ヽ，一ヨく３一 い ■● α ０ま”お” ０ ●‘● て ●■バヽス一 ヽ● らヽＱ 無Ｌ一 ０３一夕おコ ｏ ダ着ざ一 ●く０一 ｄ”ｎ ，ｏ ●” ” ﹃ ● ， ● ● ｎ く ｏ ＞綸 ぞＳ ａ 一 ヨ，一 ヨＣヨ■ヨ０こヨ一ョ︶ ♂ ﹁ｏ，３ ﹁●富 ヨ ２９ ご∽ ョ﹂Ｏｏお ュ﹁一 ぞｏ一●●，一 ヨ ８ ， ４●ヨ“営 ， ， ︵ ﹂Ｑ 一 ｏ■９ ヽヨ ａ 一 一０ ま ２■ｏ一“β ０ ¨ ¨ こ 一 ヨ ヽ ｔ ﹁ ・ ∽， Ｉ ８ 一お滲 将 Ｉ Ｂ ■ ヨ ａ ♂ ヽ” ョ︰ こ ｏュ ョ ｔ 諄 ォ ゛ Ｒ ｏみ ０こ ヽ ︵ ■ ２ ■くヽ■ヽお ざヽ ，お ﹁ ”お３ ざ 、 ■ ８ ｇ ａｍ〓 い‘ Ｅ ａ Ｆ ＾ 汗 営 ２ゝ ″ ヽヽ ﹁”庁 ｉ ８ Ｓ＾一 ５ｏ¨ ｏる ， ゴ ■ ■ ，層 一一 ｍｏ●ＯｏＪ ●需 ・■ ２ ュｏ， 質，コ∽Ｐ ａｏ● コ スｏ● ・ぞ ﹁ｏ ｏ﹁０ご＾ ２ ｎ一 営 コ ギ 守８一¨ ２ざ Ｐ ，●´ ぅ０﹁ｎａ〓 ﹁ 置 ０●︲ヨ ２ｏ〓 ●“ ｏ●α Ｏ●ヨ”晏 ﹁つＯｃ●ヽ ■ｏこ 一 ９” ｔお ヽ●●一 ８ 下 Ｑお。８ くヽ 一 ８ 、■ 〓 ●〓 一〓 ｏミ ●一。 ” ■ ，ｏ■ Ｒ Ｉ ●２ 号 〓 いｏ●ｏＲ ｏ一一一３● ３●”ョｏ∽一 一 多 ０９ Ｑ 〓 ＾ ぞ β資翼 一 一 一 てず” ●ｇ ９ 〓¨ 一´ ３ ‘ｑ ｏオ∽ お０♂ ヽ ﹂ ヽＳ︼ ＳＲ ｎ ‘Ｅ ８〓ユ● ゴｏまヨσＱ， ３一 〓ｏ ８一 ３︵ 一 轟 ３ む ∽¨ ０３ ■ ， ３ ・■ ヨ 一お ＞ ” 二 ｏ澪 Ｆ ヨ 計 ，■ ａ ２ ｏ一豊 一 ずヽ Ｘ ■ｏｑ〓 ， ｏ ，３ａ σヽ お 一 Ｒ¨ ｏ３ Ｆ〓 ８ ﹁一 舞 ｏ一 ２ 一 懸 〓 υ ｏ一 ｏ， ＯＩ ３ ８ ２ 一 ２ 〓 ｏ， 温 ， 滲 ８ ●い， お ■ ●お リミ ∽ら こ ■ｏお ３ 一 ↓〓 ョｏ７ 〓 ２ 一 すＯα お ｏ●■ く，ユ一庁 営 ＬＶ ´ メュ 営 ，ぞ 一´ ヨ ａ´ すｏ コあ´ ｏ﹁， ｏ ゴ●ヨ げｑ ｏ﹁〓ｏ， ど ユｏ●一 お ０●イ 一一 げ０∂ お ´ ﹁。 Ｌヨ 一〓姜 ≧ θ ´ｏ Ｒｎ ｃ ” 。。 ●講 ０こ つ “ お為 だｉ 増ぅ Ｏｏ●●こ ０■ ２一 ● ， デ ”ョ”ぞ∽ザ ζ一 ′，ｏ奎ｏＯ一ｏい一 Ｔ一 ０９ ・ 〓ヽ■ ● 一 ５ ω∞ 一︵ ９一 Ｓ︶ ８０ω３ ま ︶ Ｓ︶ 一Ｔ Ｏ一 ︶ ● ０す０●＾ こ ０ ●０りヽωＯ Ｓ一 ８０ ３〓〓 ∞５ ｔ ｅ ︵ こ お一●０こ ｏ３ ︵ ５ ３一 ︻ 、 こ ０ 一 ヽこ ●０ ０ない ｇ︶ ８掟 ヽ ０こ 〓 ■●一 ５ 一 ξ︶ 〇一●●８︶ ， 一Ｏ ８■ヽ ヽ８︶ ０い ｔＢこ ０︹ 一 ０さ︶ ３史０い ■一 遅 〓４０２ 〇一０もお‘ｏｃ一一 さい ０● ３うい 添´ ∞ ｔ ａＯ●Ｓ︸ ・ 一 ´ い ０き あヽＯ ｒ︶ ＺＯ ´ ００ω ● 一●‘ 一 一０一Ｎ︵ 杖 ，こ Ｃ●〓一つたｏ ３ ｏ■ 一０ぎ ︺ 一， ６ ●夕 ︸ スメ ■ ■ 一 ■ ，２ 線 一一■ 一■ ■ ３ つ∽き 〓 コ・お Ｆ ａ ｏＯく３ 〓 く０一■ く０ 一 ■一一ｄ ω Ｓ Ｏｏ 重 ８︵ ｚｏ ヽ０︵ 綸， ０一０こ 一〇 こ こう＾ ０一 ｏ ● 一６喩こ ∞︵ 夕︶ つく ，３ ヨ ３ ´ ｏ一一 一一Ｒ ９ ＞ ´２ ２ ｏ﹁ ＮＯりヽ ”Ｑ７●﹁ ´〓 ”∽ど いざ ●” ‘ｏお Ｏｏｎｃヨ ０ヨ ｏ０ Ｆ¨ ‘ｏ３ ζ Ｑ い０つぃｏう。ド ●●●● Ｎ●８ ｐ●一８ ●■ 〓 お ， ｏコ 〓 ０〓“一 一つｏヽＣ一 ヽ一ｏ〓 Ｊ ● ３ 粋ユσ〓 一 ｏｓ Ｒ 一 ３ み ど ∽一 ｏヨ 嵩 υ３ ● 毬一 ‘ｎａ ８ 場 ヽ二 さ︶や０ヨ Ｑ● ＣＰ 〓８ 一Ｏａ 一 Ｅ ， ８３ ０ Ｎ ｏＳ ︸っｄヨ ”﹁∽，＞ デ●■ ・∞００ 含 や ﹄５ ︺う８ ヨ ︵ 当 ∽ ︺， σヽユ ︲ り ・ ヽＮ 貧 ヽ マじ ゛ｏ﹁ ¨﹁∽︲＞ ‘くＱ 餃ョ→ ｒ２ お ・０●Ｏ Ｇ も ５ ︶ ´ ｏヨ ＞ ゛ ∽ヨ ´﹂ｏ● ≧ ふ り曽 ︵ い お こ で ０ヨ のエロ ｓｎ′ビ ０す０ 全０ ・ ︵ ９ ２ こ っ６ ヨ “﹁ｒ ”お ｓ ｍ５， 〓 “ヨ ”二 ﹁，●０ 口＾０● ヨ０賢” ”，お一 一ｏ ＞０ ， Ｌｏ ３ 〓■〓貫 Ｓ ・ ″¨ ■ ８〓 ” ∽ ８ ０ 悪 ● Ｊｏ ュ 一 ″■● ″日， ■０ ０ ヨとｏ ぞュ■ｏ霧オ● 〓，層ヨｏ さ︸ 営， 男■よ い０マ８ ， ︵ 〓ら ，，６δ崎 さ 一８ ざＱ ３∽ 常 〓 鴇 ＡＴ Ｒ ヽＳ ２ 一 ８∽ ａ ａ で ３ ・ョｏ，ぬ︻ ´ お ∞ε 〓 ０浄 ， ２ 〓 〓 色 や●´ ｏマ ︵ 〓・ ，３ ● む ＯＳ︶ｎｏ５一一 一 ● 澪０ い０●５ ｏも多 ｏヽ●ヨ，Ｑ Ｏごｍ５９ ０ ，，α 年ｎ思，ａ ”〓ｏｓ” ■ ０ ●一３，Ｐ ３０ ﹁ｏ﹁〓営ざ︺ 〓 ∽ 償みいｏ”■ ●ｃヨσＯ﹁０﹁ＯＲぉ●● おぅ０マ〓へ ヽご〓〓＾＾ 憑ｂ一Ｐ，ｏ● 一ヽや♀し ０ ぶ ８ ゴ ｏ＞ｃ＾ ｇ碁︺ ｂｒヨ ”一３ ヨ●一３ ８ ０ Ｎ ８ ｏＯ澪 〓 ■ 〓 ０一 ３¨ き ︷ も ３ ︶り０ いこι 壌 晨 ｒａ ■ ギ ヤ ざ ミ¨ ど８， ｏ ユて い 一 ´ ●５ ︵ 一 ∞ ｎＣ ０ ‘二，︺０﹁■営ｏ ｉａ ●■ｏ ヽ● ∽ ，ｃヨ● ■この ００さＯ ゴｏ ●イ‘ｏ ｏ ｏ コ‘ ヨ■ｎ ｃｎ ，・ ゝ０， 評↓８ヨお澪● ＞ ″凛ｏ一 汀 ﹁３ ， ● ●８Ｐ ８おュ３ ｏ﹁一 み︼ Ｓ一 ｏ ∼ 鸞ぉ〓諄﹁薔一 ミめ ス一 凛ａご一 ０ ■ｓ ヽ ・¨ ■ ，３１一 ｔ． ■ ∝Ｑ ■じお こＦ¨ ¨ ¨ ヽごユ●〓● ●一 く ｏ ｏ８■● ｏ ス争ｏ ■●ヽコ ヽ■３一 ご０ 〓０︶一 コ﹁，″ Ｐ一 一 営●コ♂一３●● ５ｏ，す 一 〓い ｏ ■∽︵ ０製冒， ”∽ ８ 〓 τ・ ≦オ ヨ〓５■〓 ﹁∩ も、 〓ョ︲ ｏ 澪゛ 〓い ヌａ嬌ｇ て 黙 ０澪 ａ ざ すｏ一ヨ 摯 ３ 橡 賓 ︲ 一０●一●● ３ ●ＯＰ ヽマ 増 ユ 〓 Ｑ ｏ ”０■ ， 一 一 ● 〓ぞ ３ｏ﹁ｎ、■ ８ヨ０ じ グすぃ ８ｏ ｏ ０ ０ ５ ０ ● 鯰 聡〓う 一 ¨ ョ〓ぉぉ﹁。３● 員一 ■ォ● ヤ ●● 〓。 ﹁０ 一 ゴ ｏヨと〓 ４ Ｒ ，ｏ﹁Ｑ も ヽ ８ ョお さ３ ＾ ■ ８８し ，ξ ︶ 〓ｏだ ﹂０ヨ，デ″おα ６ ●Ｒオコ● く〓０ す０﹂ ヽ一 スヽＱヽ おう０ヽこ ０ユ０手 ｑ 〓ｏｏ０８ ｇｏｏ一８ ´ｇ ∂ ″ ｇ ｏつあ＾要月も 〓ど うま さ﹂ ギ Ｒ も■ 〓 Ｒ ″二 σｏ一摯 ， ωＯ一・ｏョ テＲ ９ 一 一 い０一´ お ヽ一Ｑ 共 Ｓ ａ さ 一 ０コｇ ´ａ ， 一 ”︼ ■●ヨ ”″″＾●２メ”¨ 一 一 ，Ｏｃ， ヨ ２ 一 ヨ´ と ｏ●・り ｏ∽ き， ど一 ｏロニ ´ ？ ｎュ０ ３ ８９ ＞” Ｓ一 ０ い ω︵ ９ω ｏ ωい ０︵ ３い 夕一 ｇ一 一 望だ日 ヽ ３■●一● ５ 一穴 ０一 Ｓ一 に ０一 ３，一 ０つ０， ご，■， 一 ∪ お ０一げ“●ｏ● ｏ﹁●色ｐａピＬ ｏ●● コ﹁ も ５ ８ ヨＢ ■ ●メ ∂ ”＾ ａ 月 ８ ａ¨ ﹃讐 ∽Ｐ 一一 ０●〓 ｏお Ｒ Ｆ ﹃ 品 ︷ ０ヨ一〓〓〓一 一 一 ｏ ０４ ９う０●ヽａ 一 ●一イ”一 ● ０一ｏＦ 一 ●，〓Ｃ＾ ０● ↓，ｏ一 ヨくｏ′チ ？ ａ● Ｆ 塁 〓 ２ αａ Ｆ ´ 汀 ご一 ξ ３ ぞ 静 Ｂ ■ ｏぎ ュ 〓〓ｏ， Ｑ ｏヽ５， ，● た日，３ ｏげ除 ■ ｏ， ︶２ ●〓ｑ ｏ∽‘ヨ ヨ，■Ｎａ 〓０”ｕｏ”ＮＯｏ ●６ 澤﹂‘一´ ｏこ´ ２″０ ●本・ｏｏ●＾ ” ヽ∽●●一ｏイオヨＯｎ尋´ 一ｏ一ユ一 ＾ ざ●∽ ０● け ｏｏＣ びｏま 澤 ”２ｏ３ ● ♂ ヽ ●”３一３ ，０● ︺● ●警 ｏ“己 ■ ∽卜 ●くｏ温 ・●︲ ■３ ● → １ ■ Ｏｅ → １ ■ 一● ｒ≧馬ｎｔ﹃●営い き〓ヨａユ● ９ ，窮﹃ ‘ ¨ ａヽ 一 〓庁二ｇ一 ■ ”●ｏ〓一 ″り ♂∽ ざ●︲ ‘ＸＯ■ 一ごｏｏｏ﹁奪 一 ２ざコ♂”０おくｏ一●ｏうｏ”´ ■●０一 ３●゛ ■ ， 一０一 ２ ａ 讐 ，か・ ”‘ ８ 一 Ｆ∽ ″∽９ ８ ヌ ”３ ， κ” ● Ｓ Ｘ ョ ●Ｉ ¨ 凛 ●８ 一 ゛〓 一 さい 一 〓 ０２，■●お ０コＲヽКＱＯ一 ヽ一●７一 ■ヨ∽ど 一 ３ｓＯ﹂∽● “●■●こヽあ こ〓”８ ，ｏ●留〓ごわ ｏ︰ ３０・ヨ︶・ ｃＮ ´〓，と２一 ８一 ごお” ｏ ， ■・■﹁︰ きヽｃＸ ６一 ″けど ︶＞オｑ ´ 〓ヨ一■ｏ Ｅ一”‘８一 ”営ヨｏ ■ ａ ，己 ∽輻 す ｏｌ ３ ｙ 〓 Ｐ Ｃ ｃヨヽ ３ ｔ ｒ″ ■ｏ澪 ８ ， ■● ヽ ♂﹃σ●２●ユＬ ｏｏ■ ｏヨ〓 ２６５ ０■ｏ”３ ス一 ｎｔ Ｆ ，一一 ”０﹁‘３ ぶ ｇｏ 一 Ｐ 一 一 ３ 一■，０＾ ヽ諄 ´‘ｏヽ０●ヨＯｏヽも，一 ａ 一 ︵ ＞〓 ，ミ一 ｏＬ ｏヽ“ぞ総´ ご ヨ彗●晏 ●ョａ ｓ３ｏ ３ ● 〓∽ ヨ”∽ ● 一 〓ｏ掃 鴨 潟 ，おＱａ 一 ０マ 凛 ●あ ｏＡ ２ 理 摯、 Ｊ ｏ﹁ュョけ史 ｔ● ﹁ョ﹄ ８ ●Ｒ ３●３ ０ヨ一８ ■二 〓 ０，０﹂おヨｒンド 一 一 ヨ３ ¨ “Ｉ ■８ 一 。●一０●α〓 ∝ ｏ● ●ｏ●■Ｑ ぁヽ８ ３ 一ぉ”Ｌ 、﹂ｏ３， ﹁６デ ”目 ∽〓００ ＰＸ Ｑ σ●さａ 讐ｏｏｘ，ｓ■●ヽ ﹁ｏェｏα Ｏ﹁一一３● 〓 ﹁Ｓｕう０ ■，●∽ ｏ一一 卜 ρ ＯａｎＪω”■ ヽ こ ０姦 、０ ■０お ‘５ＱＯ凛 ｏＦ ” ″一■ 一 ｏくｏ８ ｔ 負 ∽●凛 ０■ ｏ、いｏ一 ざ 一 。一コ●一 α一は，ｏいｏ一 ■，ヨｏ ﹂ Ｌ ﹂﹁一 ｐ” ●α口αＯＱ 〓，ｎ〓 ●６ざｍヽ︲ ・ 汗 κ ●ｏま どｏ一 多ｏ●コ■ ィ ■ ＞Ｌ ｏコｍ¨ ｏ， Ｌ ８ 貧ふＳ Ｒ ３ ８ ︸ ●●ゼ 円 Ｈ８ ，お 輛 ョ′ 〓ｏお ●〓 一 コる ０８ ３ ´ 一 ３ ， ぉＢ ，ａ ８ すｏく一ｏメ﹁ｑ一 一●ｏ●０摯 ″，ＦＯ●ｎ４ ３ ●一コ ュ０，お●２ざ●〓 ， ０﹁計● Ｚ●日″一■０﹁■，●資ピＬｏ●ｏつｏ■つ，ＬＯ●＾ ︼汀 廊Ｉ ｏｏ■ ∩ も ﹃ ｇ ， Ｐ 一 ¨ Ｓ・ ８ 一一■ マ ●■ 一■３ ， ０ ︼ 〓 ”ヨツ ■一“ＯＲ いお Ｌ ８ ∞ ︵ ■¨ ヨｎＯ¨ Ｄ， Ｎ一´ 轟 ， Ｐあい ｏ諄 鴨 富 汗 〓 ８ ﹁〓 ９ ″ 〓ぎ えｏｏ一 お ０貿﹁ ち ﹃ ●〓 Ｆ 輻，ユ Ｒ ´ ど， ぎ〓 ，い０〇 一一´ 一 ｏ●● ０ヽあ∫ ︶滉Я 一 くａ ｏ３ぞ ｏ●ｏ ■月 七 ﹁ υ一 一 ド Ｓ● ０●５ 一 ９ ヽヨ 凛 ョ 一弯ｃｅ ■き ， ３∞もヒ９お ︵ ス ０ぬ一 ヽ ａ一 ミ ｏ ８ 争 ヶ ■ Ｓ ， む 一¨ ｏ， ﹂ こ ３ ● ︵ 一 ふ ”鷺 ︹ ︺ゆ一 ●５ 熟ｏ 、ｎｔ﹃ｓヨ ″ｇ も ヽ ｖ ■一 を， ■ξ ●どＬ И ｏ 〓αヨ０ ”＾ ¨ ↓〓 彗とｏ ２秀ａヨ‘一 ︵ ” ｏ﹃ ● ｏ ｉｎ＾ ヨ ぞ Ｒ３静ョ∽‘す ｏ ヽヨＰ一 一 ォ亀 一らヨ， お ｒａ ，■一 ヨ” ∽ ｏ 〇ｍ ８一 ３ 曼 ε品●ｏ ヽ‘胃ｏご鴫 ２一 まａ 一ヨ ●色 ３＾ ■ｏ お０ぞ ３０ ，● ヽ ８● ´ ， ヨ０ ８マ 営０ Ｒ∽ ｏ ， プ ６ 薔 ´一 ｇ ｏ ﹁ｏ８ 一 秀 ａョ９ 一 ■ ● ´ｏョ う↓∽ 冥 Ｆ 〓 ｏュ ● 〓 一 一 一 ８ 一 ０言 ３ ２ ， ａ ョ ， デ ゴλ ヨ ？ 償 一 ｓ ， ご ●一 営 Ｒ ■ ，■ ，■ ０●● ｏＯ︲ヽ●ヽ■ ２ ２ ● 、、 〓 ０一︲一一９ 〓 ざｏ て ，一 ■ ３ 常 一 げヽ 倉 ョ ． 庁３ ９一■ハ ００ す ■ 一﹁ぶｏ ＾ ０ ョｏ ﹃ ● ８ざ要 ，● ■ヽ 雙さ● ■冷 ３ ■ “ｎｔ﹃ ８ョ一 ９ ９︵ 一■喜 一 ●〓 ∞ おａ くｏ ■８ 送 ｅ ，０ ３ａ露 ＞一 ユ一 ゛ ０ ０ い´ ０ ０３・０● ゛ く● ｏＺＯ ヨげ ｏ ”゛ ｏヽ ︲ ｏ ，２Ｑ ヽ● デｏ︵ ■， 二︶〓ゴｏ‘● 一 ざコユ 汗Ｏσくわ コＣ●τＯ 一， お， ● くｏ づ ｏ 〓０ ３８ ｏ ０ ●０さ月ｏ 一 一 ｏ 〓 ヨ● ７， す ， ”” 一 る。 製 ♂”ぎｏ Ｒく０ 増ｎ 一３ ︶３ 鮨 ５ ３ ヨ 一ＯＲ ●● 二 〓 Ｆ ， ８ ‘ヨ ９ ， ス ユ２ 写 ０日 、ε ８ ｕ●ｚｏ ００９ κ営Ｆヽや 鴇れ、 ，ｏ言０一 〓Ｑ， ０ヨう ｏざ鳴ヽ９， ｏ， ゛ ”″αげくｏ ョ ｏくｏ５Ｑむ﹃資● つ う， ●ｏ 一´● ●Ｃ 〓 ■ ２ ● ● ，コユ 一‘晨 う曼 ｏ〓 ｎ 一５，コ ３ ■ ぎ く３ ｎ〓 貿 ８一 〓０ 一〇３︼ ス営ざ， 一 置， コ一 員● ●● ‘ ●湧■， ¨ ぃ０一５ ぎ ０一一 一 ｏ Ｒ ≧ ヽ 〓 ヨＦ 一ヽ ■ 一 ３一 おｐＯ ■ ｎ くａ 一︵ ﹂ ，コ０，１ 〓Ｏｏαｏさａｃ２ ∝ｏさら 〓一ぃｏ＾ＮЦｔ〓〓Ｓヨどい ０ユ ηｏ σ● こｔｆ８コ“３り０﹁営¨ ａ ｏ５●おもぶ ｏ﹁３ ● 一ｓ ・３Ｆ 一り０■一 どい ざいお〓︵ ３●０﹁∽ ６ＱＯ﹁，●●●一 ，〓∽ 一 ｏヨｎくｏｎ■ ，＾でヽい ”︻ ”︵ ｏ一 ｎ４０ｏ日﹁０●●●＾、ｎ”一 ０いヽ ”﹁Ｖ¨ ｎ 一 くｏ〓Ｒ ３ｏコ月も■﹃●ユ●〓● ご お０やｏヨ Ｃゴｑθ● 澪 ヨヽコｃ計０ ∞ ヽ ５どヽ 日ｏ ■ヽ 〓ヨ一︵ Ｎ ８０ ｏ ８， ｓ‘ ８３ 靭 υ 〓０ ， ”ｒ↓●貧 ω一Ｐ Ｏ，ＯＳ ︶モｏお ｏ９ ‘２■ Ｈコ海〓と ０■ぐ ｏ、ｉ ｎ ﹁●↓， 説 ﹂一 ａ 二 多 ギ¨ ■８ 一 と ｏ● 〓 〓 〓 ３ ，” ＾ ” 〓 Ｎヽ鶴 ”０デ ”薔 ∽ くｏ ０● ＞０ ﹃ｒ﹃´ 一 みｏ２ ● ●， ど一ｏ ●ｏ ■５﹂家︼︲ 番●ｏ ０● ，﹁會〓おェ∽ど∽ 一 ど∽ ざコ´ ｏ● す０，´ Ｏω ００Ｓ ｏいヽ一ωヾ ●●●∽ 多 Ｏｓ＞” ０いＳ のｒ ｏ¨ ギ一 ＯＳ Ｔ Ｓ〓 ♂ 一一 ａ ‘一 ｏヨ ‘０お ３ ８ 〇一 ”´ ■●げイ じ一０﹁てコ一 一 〇３● ０３δ２ 一 お ■ ど∽ ●〓 いい０ ●５ ｏ﹁一一９゛´ ０， 一ＯＳ︶〓々ヽ ｎ一 ａ ヽマ３ じ て ■ 津 ０〓 ＞翅 ﹁ｏヨ げて お一 ヽ ｏ´ 一 ■●８， ｏ﹃＾Ｓお０ ６ ﹁０７”ド↓ ●●●彙ば∽ ０， ＯＬヽ コぐ０つヽ ０ ３● さ ０〓００Ｌ９ＮＳ︶ ■ｏス ｏすり３●ａ●一● ■●●一＞﹄●さ６ＮＳ・０い Ｏｔ ０３σ，堅く‘●ぉｒお０８ ，″”日′ ”ｒ︻■，コｆ ，５０●● ら﹂ ， ‘α∝● コ∽ 一 Ｌくの８‘冷∽∂︻ ０ヨ σ夕ａ ｏゴ ，ｏｏＯ総そ２一 ｏ● Ｒ 〓︹ ９，， ﹂ｏ ●８ ｏ﹁ｏ， 告一 ●０５０２¨ ｃ３一お一 ●〓こ一８ ，ｏ●摯２Ａ ｅョヌｏヨ∽● 一 ３ ヨ一Ｆ ●お ︺ Ｚｏの場 ″ ｏ、´ ， ●ｏ２ 一ざ ﹁‘” 下庁‘蒙ピ お 〓 ・¨一 こ ｓａ ，Ｓ﹂ ヽｏ Ｑ●臓 γ Ｏｃ●● ”の↓，ヽ日 〓 樹 ●∽ど ∽ざ ３ ●■ ｏ富Ｏｏ●ｏ， ０一 ｏｏＯ■す０＞‘●０一３ ８ ｃ●２ ３ョＬ Ｒ一 ，■３ ワ‘０テ ，一 ■ ８ ８ ︶０今 日 ｆ ８ い ｏし０ ゃ０３ ”︺ ” ５ｍｒ■ で０■旨 ミ ヽ一 〓一 80 〓ヽｏミｏ‘ 嘔ご３一うｏ、ヽごｏ一 ０●一わ■ ド●一” お ユ一ＯＬ 摯笙■一 ｏ一一 Haenovigilance of photochemicaltreatedplatelets 319 Tablc2 Clinicelrha€ctrri3ti6 ot advcEcevrntsIAEI On a pcr-transfulionb$ir, (0,b= r x 100/7437) AF att“ buted to phteにts Anv AEs (ATR〕 。 SAr t 。口。 meF・ S(く01%)010 007ol Numberwith et laa( oncrvant 63(0 9qo1 55(0700) Signtsymptoms' 8 ( 0 1 0 / o ) 0 ( < 0 1 )0 7 。 O(0%) ‐ Fwtr 4510601〕40(OSOb) 2(く Ol%)― Chills 2(く Itching 0 : , % 〕2 ( く 01%〕 0 ( 0 リ ー , k 0 1 0 7 o ) 。( O S o l 1(く01%)― Hypotansion 14(020o) 14(02%〕 0(0%) = uiticarie 5 ( く0 1 % ) 5 ( く 0 1 % ) 0(0%) ― SkinEsh 1(く010b)‐ 8(01%) 0(く l110o) oFpnoca 1 ( く0 1 0 o ) 0 ( O O b l 1(く010o)= RespiEtory distrcss 81● 1 % ) 5 k O i O r o ,3 “0 1 % ￨ ― Neu*a/vomlting 6(く 0,Oo) 1(く 0(030 Lowcrbackpain 01%) ・ pain 1(く010o, 1に 01%) O100o} ‐ Chcsvabdominal Shoct Tpchycardie Other ￨(く01%) 。 0“〕 4k01%)0(く 01%) 14102%) 11(01111 4(く010b)― ,((01%)― 3(く 01%)― Serious adverse events fouowing plateld't tansfuslon 0n. pcr-pati.nt basis, (90= D x 100/1400) Anv AFs(ATR)。 45(320b1 SAR` to plateletsIや 39(2 SOrc) 4(03%) 0(00¨ ) 7(05%) 5(04%) 00%) ― 1 ( 0く1 9 7― ●12噛 23● 0呵 o〕 1(く 01%〕 ,(くol“〕 0 { 0 % ) ― 1(く 1(く 01%)O101●l 0197o)― 13(0 9Cb1 13(09“〕 4 10 3qo1 4(03%) 8106%1 61040/o' 1(く。1%)0(0鳴 510:4%l' 3102“) 2 1 1 1 % ) , k O 」% ) ikO,￨￨サ ,“ 0'%) 3(02¨) O10%) O1020711 2(0,qol 12(09ql1 10(0700) O rO%) ― 0 001ol ‐ 1(く01%, ― 1に 01%)― 2(ll i“ 〕‐ O100bl ― o“nl _ 3(020b) ― ,(く0,・ll ― 3(02噛 ■ . long-tarh life threatehihg, immediate lifc thrcetcningor dcath. seriousadvcr avant(sAE)r rrlatcd.or rclaredto tT-PLTt6nlfusron. tausal rabtionshipthatliaspo$ibly.r.latcd,D.obably plr AE, cxa.cdnumblrotA[ dueto multiplcobscwadsiqns/symptoms "Nunbcfofsign{symptomsceh Characteristics of clinical signs and sJmptoms associated with adverse evant On a per-transfusionbasis,the most frequently observed (> 0.1%ofthe total 7437transfusions) were symptoms/signs fever, chills, urticaria, dyspnoea,nauseaand/or vomiting {Table2). Tbe individual incidenceof eachof the following was< o.l%r itching,hypotension, skin rash, signs/symptoms r€spiEtory distEss,lower back pajD, cbest or abdominal pain, shock atrd tachygadia. All additional symptoms includedin thc categoryof othet such as refractoinessto plarelettEnsfusion,hypertension,cephalea, pain in the leg, flush, malaise,cyanosis,oxygen desatuntionand yolume overload werealsorcported but with an individualincidence pnncipallyas of Ie$ than0.lqio. MostofATRSweredescribed Cradet chillsandunjcaria{Table2). On a per-patientbasis,.the most frequentlyobserved s)4nptoms/signs PO.5% ofthe total l40O patjeDts)were fevet thills, unicariaanddyspnoea(Table2).Apprcximately o.l-0.4olbofthe population(froh 2 to 5114oolexperienced the following sigN/symptoms:skin rash,nausea/vomiting, shock,iowerbackpain andtachycardia. Clinicalrefiactorinss to transfusion,hypertension,,headache and flushing were additionalsymptomsreportedih the categoryof'other: Less than0.1q/oof the studypopulation(only I / 1400)axp€rienced thr followingsigns/symptoms surb ashypotension,itching, respintory distressand chest/abdominalpain. Symptoms suchaspulseincrease, legpain,cyanosis, oxygendsaturation, malaiseand/or volume overloadwere also reportedin the categoryof'other'. Most of the ATRSconsistedof various combinarionsof feverl0.4o,b). chills (2.00/o), unicarla(0 9obi, (0 2ry01. skin rash(0.30b), dyspnoea(o 4o,h). nausea/vomiting tachycadia(0'10/0) and otheresymptons{0 7%)(Table2). 0 2008 The Authorlsl "θ “"iS(2008)94,315-323 on o 2008 31ackwc‖ Publishing ltd:,ν レ sα Joumal compna● During the cotrrsebf this suryeillanc€, five seriousAEs were repoft€dfollowing transfusion of PCT-PLT{0 07%, 9io,bCI:0.0-0.2).TheseseriousAEs wereassessed by the investigatoFas being 'unrelatedor probablyu!rclated:to the PCT-PLT transfusions andwerc attibuted to proBression 9f underlyingillncs. PatientB0l-201 wasadmitted.tohospitalfdr a presumed pulmonaryinfectionpostchemotherapy. Additionalcomorbidltiesatthe time of admissionweresepticshock,acute r€nal insufficiercy, neutropenia and thlonbocytopenia. Intnvenous(i.v,)antibiotictherapywasinitiatedandmultiple transfusionsof blood products (including PCT-PLI were administered, one hour after administrationof the second plateletunit,thepatientcomplain€dof dyspnoea, respintory wasfoundto beh)rpolensive distress andtachycardic,-severe voluDe overloadwas detemined to be the aetiolog/ and treatmentwith oxygen,diuretics,and dialysiswas initiat€d. Theeventwasawsed by the irvestjgatorto be unrelatedto the PCT-PLT tnnsfusion. PatieDtJOI-382experieaced chjlls,nauseaand sudden with PCT-PLT, hypoterision dufingtransfusion Priorto this, the patienthad K€ived at least four PCT-PLTtrarsfusions with no AE.Thf tEnsfusionwasstoppedandtbe patientwas treatedwith i.v, fluids and iecovered.Four days later, the patient*periei:ceda !(ond h,?otensiveepisodeaftertans: fusion,whichwasspontaneously resolved.Subsequent to this, the patientreccivedl9 additionalPCT-PLTtransfusions withoutanyclini,calsequelae. patient This did not rKeive any angiotensin-converting enzyne(AfE) inhibiton.Basedon the patient'shistoryandtbe lackoftransfusionreactjonwith the subsequent tnnsfusions,the investigatorasessedborh of thes€eventsasppbably unrelatedto PCT-PLT transfusion, PatientJOl-516 wasadmittedfor ishaemiccardiomyopathy and underuentdoublevesselcorcnary artery bypassgraft (CABO).Thepatiot's postopentiverecoverywascomplicated by a significantdsreasein bloodpre$ure,which occured lO min afterstanoftnnsfusion of PCT-PLIDespltevasopressor suppoltanda 6-minpedodofcirculatoryarest,thepatient's conditiorcoDtinued to deterionteaId hr died,Causeofdeath wasattibutedto an aorticdissection with majordisseminated intravascularcoagulopathyand mesenteicjnfalct and was assessed by the investigatoras unrelatedto the PCT-PLT lransfusion. PatientJ0l-780experienced a hypotensive episode, cyanosis, oxygendesatumtionandrauseaapprcximately30 nin after receiptof PCT-PLT, The patient receivedoxygenthempyto treat the eventand rccovered,The patienthad receivedtwo unitsofPCT-PLTbefore and oneunit afterthis eventwith no adverseRactions.The patient had a history of hypotensive episodes.which occured in the absenceof tnnsfusions. Basedon tht patient'shistory the eventwasassessed by the jnvestjgatorsprobablyunriated to thePCT'PLrtraDfusjon. Risk factors associated with adverse event The risk for AE wasnot srelated with the patienrgender, age,or antigen-matching, The risk for AE for patientswho alreadyhad bren transfusedbeforethe fi6t PCT-PLTtnnstusion appearedtrendinghighei comparedto patientswho did not haveanytransfusionhistory;howevecthedifference did not reachstatisticalsignifrcance(P = 0.0675;oddsntio: 1 875; 950/0 platelets CI: 0956-3 548).Bufry:coaGderived wercasociatedwith a lowerrisk for A! compaEdto apheresis prcducts(P= 0.0305ioddsEtio:0.473;950,h CI:0.240-0.932), were ofsimilar risk for A-Ecomparedto Iradiated PCT-PLTS (P = 0.0848;oddsratio;6.344;950/o non-iryadiated PCT-PLTS Cl; 0.775-51.862). No trendingcanbe concludedbecause, of the total 7437platelettransfusions, only 80 PCT-PLT components werey-irradiatedin EFs-Bretagne and EFSAuvergne-Loire,Haematolory-oncology patients rrcated with conventionalchemotherapywerf at a higherdsk forAE compared to theotherpalients(P<o.O0o1; oddsErio: 7.660; 950/o CI:3.014- I 9.457). Number of trmsfusions prior to the. nrst adverse event Among the 45 parientswho experienced at leasrone AE, repeated exposurcto PCT-PLTdid not appearto increasethe likelihoodof a transtusionreactionffable 3). By using the non-suryivaiatralysismethod(a subsetanalysisfor patients with any AI only), the meannumberof transfusiorisbefon fi6t AEoccurencewas8'8 1,10 1 (median= 4, minimum= 0 andmaximum= 37). ［∞ On a per-patietrtbasis,45 patients{3.20i0 of 1400patientsl who receivedat leastonetnnsfusion ofPCT-PLTexperienced the 68 AEs followiDgPCT-PLIlransfusions(Table2). 0nly the 55 ATRS 39 patients(2.8%of l40Opatients)experienced attributedto thc PCT-PITtransfusion.Foui patjentsexpedencedseriousAEsfollowing transfusion:however,no causal rclationshipto PCT-PLTtrarsfusion could be establjsbed. All AEs regardlessof rhe relarionshipwith the PCT-PLT tmnsfusionoccurRdwithir 4 h after the stad ofthe platelet (meantime:0.f t 0.51h, 0-3.3 h).Themajority transfusion in patientswho.weR ofAEs(64,or94.l% of68 AEsiocc-uned not premcdicated. The other four AEs occurredin patients who were premedicated with antipyreticor antihistaminic drugs,or conicosteroids, 320 J C Ossclaereral, Discussion In accordance withtherecommendations madcby thepanelof theCanadian ConsensusConferenc€, an adive haemovigilanc pmgrammehas beenimplementedin Europeto document the occurrenceof AE following transfusionof PCT-PLT{61. To.date,two reportshave beenprepared.The first repon was on thetEnsfusionof5l06 PCT-PUIcbnponentsadminist€red to patientsjn frve Europeancentresfrom october 2003 to December2005[+].The secondreportasdescribedherewas on additional 7417transfusions ofPCT-PLT admlnistered to patieits in sevenEurop,ean centresbetweenMay 2005 and January2007,This represents a total of I 2 541 independenr transfusions documented to date.Theitarcno overlapsofPCTPLTtmnsfusions prcgnmme. reportedin thishaemovigilance Overall,th€ incidencsof.ATRattributedto transfusiotrof PCT-FLT in bothofthe haemovigilance reponingperiods was infrequenteither,ona per-transfusion basis[0.8V0frnt period 0 2 0 0 8 Teわ oイ s) Au■ J o u m J c o m p u a l o nk "od l2 0ヽ ぐ P0hu8lЫ n Bg l aL″% t d",bレ i“″ s12008194,315-323 Haemovigilanceof photochemicaltreatedplatelets 321 Tsble3 Numbefof Pc[-PtTtranifusionsper patiantpriorfo thc fi6t adwr;..venf {AEl 02●● S The Author(゛ J o u d“ c o m p u a l o n o 2 0 0 3 8ヽ 1h al cn kg w dL It d P" t1 Ы “ /"aお r1 2S0a0■ 8194315-323 on when adverseevents could be reportedfollowing transfusion.Basedon the patient p,opulationsupported with platelettrsnsfusion, the studywasdesigned to capture repeated tnnsfusionsofPCT-PLTwithin patjentsto detemine potentialeffectsof repeatedexposureto this new type of plateletcomponenL A limitation of the presentstudy is the absenceof a concurrcnt codtml group receiving conventionalplatelet compon€nts withwhichro determine a comparative baseline incidenceofATR. Howwer, becausereportingis obljgatory, the expectedoutcomesof this activehaemovigilascrstudy are the incrcas€in ciinical expeience with transfusionof PCT-PLT,the d€tectionof unexp€ctedAE following PCTPLTtransfusjons in patientpopulations and for indications that wtrc nol studiedpreviouslyin a fomal clinical tdal environmGnt, and.theestablishment for ofa safetydatabase future referene. In the cursnt study,which was specif:callydesignedto captureall gradcsof tnnsfusion reactions,the prevalence of ATRpertrarsnslon,wasat the lowerrangeofthoserepotled in studieswith conventionalcomponents,Prior exposureto PCT-PLTtrensfusiods did notincEasethelilelihoodofanATR. TheoverallincldenceofATR wasIowerthan that previously reportedeitheron a per-tnnsfusionor on a per-patientbasis. platelet Basedon cxperience in a broadpatientpopulation, prepard with amotosalenphotocheniicai components treatin routineclinicalpracrice. nent werew€ll-tolcrated Acknowledgements Thi authonwouldtiketo thankthe followingindividuals of Fenwal,formerlyBaxterR€tDEurope,who assistedin the jmplementation ofthe INTERCEPT BloodSystemat theblood centres,prcvidedcritital itrput into the scopeand designof the haemovigllanepmgnmme,andtnining ofsite pe6onnel on dataentedng:Joielynf ElameDt,Jean-MarcPaynt, Nitk Moerman,ValentineFEnck, and VeroniqueMayaudon. and statistics service Quintilesprcvideddatamanagement prcgramme. for thjs haemovigilance Thisstudywassupported in part by CerusCorporation. Threeauthors(D,Sundin;L. Lin andL, Corash) wereaffrliatedwith andheldstockor stock optionsofCerusColpontion during$e conductofthissrudy. ThreeauthosU. C.0sselaer, J. P Cazenave and0. Garraud) servedon C€rus'sEurcpeanScientifrcAdvisoryBoard. References I vanRh€nen DJ,Gulliksson il, C.".n.u. J?, Panphilon D, LjungnarP,KlUte(H, VemeijH, Kappe6-K1une M,deGreefG, LaloretM, Uow B,DavisK, MarblieS,Mayaudon V, FlmentJ, Conlan M,LinL,MeE€lF,BuchholzD, ConshL:Transfusion of pooledbuiff coit plat€l€rcomponenbpreparcd with photochenicalpathogen inactivauon trcatnent:tle eurosPRmtrial, Blood2003;l0l:2425-2433 2 Mccullough J, VesoleDH, Benjanin RJ, Slichter SJ, PinedaA, Snyder E. Stadhaucr E, Lopez-?lazaI, Coutre S, St€u$ RG, CoodnoughLT, Fridey JL, RaifeT, CableR, Murphy S, Howard F, Davis K, Lin J'S. Metzel P, Coresh L, (outsoukos A, Lin L, Buchholz D, Conlan M: Therapeuticeftrca.y and saftty of plateles treated with a photochenical process for pathogen inacrivetion:the SPRINTli,al. Blood 2OO4i104:l 534- I 541 3 JanetzkoK, CazenaveJP, Kluter H, Kientz D, Michel M, Beris P, Ljoure B, Hastka J, Marblie s, Mayaudon V, Lin L, Lin J-S, Con)an MG, Flament J: Therapeuticeffrcacy and safety of photochemicallyrrearedapheresisplalels proce$ed with sD optimlzed inte8Eted sd, TtunsJvsloi 2005: 4t:)443t452 4 OsselaerJ, Mse N, HeNig T, Bueno JL, Cas1rcE, EspinossA, LaconeA JungeK JacquerM, FlamotJ, Consh L: A prospmivc . obsewatiotralcohort safety study of 5106plalelct iransfusions prepared with photochenical treatn€nt, Irarulfusior 2OO8l doir io.i I l l/j.153?-2995.2008.0t643.x 5 GaFaud 0, Fabdgli P, Tardivei R, Goueec H, Waller C,Merdel 1, : Raidot JP, Kardel C, Isola H, CazenavcJPr Hemovigilancefor tmnsfusion of INTERCEPTTMplatflets in routire thenpeutic use: expedenc in Etablissenrnt FEncais du Sang (EFS)blood .€nt€r$ Yd S4r9 2007; 93{S I )r32 6 Kcin HG, AndersonD, Berlardi MJ, CableR, CareyW, Hoch JS, RobitailleN, Sivllofti MLA, Smaill F: Pathogeninactjvation: naklng decisionsabout new technologies,Repot 6fa consensuS 'conference. Trd{'tusion 2OO7 : 47 :2338 -2347 7 Andrcu G, Morel P, Forestier F, Debeir J, RebiboD, Janvier G, Hen€ P: Hemovigilance neMork in Francei organizatjon and anal)6is ofimmediate transfi$ion incident repofrs fron 19941998.Tn6Ju sion 2OO2t42tt 356- J36. 8 FaberJC: Haemovigllance In Eurcpe:now and tonotrow; In Rouger P, HossenloppC (eds): Blood Ttgns.fusionin Euope, Paris,ElsevierS,AS,200512I 3 -232 銀∞ datawerereponedfortlansfusionr€actions, with an incidence of four eventsper 1OO0plateletcomponents[0.4%),during 2 yeaF in which thr reporlingsystemwasfiFt implemented. ilunblr ot PCI-PLTtraniflsiotri Full analyrkpogulqtiod However,this may be an underestimatesinceeach whole prr irticnt untli fiEt Gcurrncc of AE (r = I aOO) blood plateletconcentratein a pool was tabulatedas an individualcomponent transfusion. Kerkhoffs Morerecently, I 11{0 79h1 era,. [l5j compared the incidence oftransfusjbnreactions. 5 t0:43ft1 pooledplateletcomponents for Ieucoreduced in plasmasnd 3 3 (0.2i oh) plasmawith additivesolutionir a studyof I 68.patients and 4 3 (0.2r%l 755 tEnsfusions.They obsewedan inc.idenceof 5.5% of 1 (0.070e) transfusionswith r€actionsfor plateletsin plasmavs. 2.40,b I (0 e%l I-19 of transfusionsfor plateletsin a mixture of plasmaand 6 {0.43%l >20 6 {o.43ob) additivesolution,0n a per-patient basis,.9.5% of patients N {non5uruivalan,lyrismathodl 45 transfused with platelesin plasmaplus additivesolutions M.en t S0 88Jl0.l had reactionscomparedto I 5'5% ofpatientssuppodedwith Mcdian plateletssuspended in plasma.Theser€sultsfufther support Mnimum-meximum 0-37 the role of the platelet additive solution,lntersol, in the reductionofATR observedin this study. Duling the conduct of this study,an interim an'alysisof vs. OTqbsecondperiod)or on d prr-patient basis(4 90/ofirst 2497 PCT-PLT transfusionsadministeredto 505 patientsin pcriod s. 2'8olosecondperiod).The slightly higher occurthe thre regionsofFrance(EFS-Alsace,EFS-Auvergne-!oire renceofATR per pati€ntin the fi6t reponingpedodwasnot andEFS-BRtagne) wasperfomed [5j.0fthe 606patients,the surpdsing,becausethe mean number of transfusionsper ptedominant recipients of PCT-PLTw€re haematolos/patient(7.8t l5:2)[4]wasgresterthanthoseobserued in the oncologypatients{45.2%);39.90,b treatedwith chemotherapy secondperiod(5.3t lo.8).All ATRSwercmildin ssqity and and6 3% treatedwith stemcelltransplantatjon. TheseproporofGrrde I or lower.No seriousAE from both studypedods tionswereonlyslightlylowerthanthosein theoverallstudy weR.atbibutedspmificallyto transfusionof PCT-PLT. population patienrs, yet onlyfourof the606parienB of ) 4OO 0n a per-tnnsfusibnbasis,the prwalenceof,ATRhasbeen (0 70,t)reportedan AE; including one seriousAE ofvolune 0/o; reportedi! the litcratureto nnge.from I I to 3 I b owevet overloadclassifiedasunrelatedto PCT-PLT transfusion,This thesestudieswetr conductedsome years ago with variabte iow rateofAE ob*ryed in the Frenchregionscouldconfibute methbdsof plaleletpreparation[10- l3]. Moie recentiy,the to the overalliow incidenceofATR per patientin this study. incidence0fmodemt€andswereATRhasbeenreportedfrom Prcm€dication in patientsdid not play a rcle in the overall thetdal to Educealloimmunizationto platelets(TRAP)study, low incidenceofATR reportedin this study.Infomation on which examined8769{latelet transfusionsin 598 patients premedication wasonly requestedin caseofAE occurrcnce. duringindudionthqapy foracuteleukaemiaIt4]. In theTRAP 0f the 68 transfusions with occurrence. of at leastone AE, study,ptateletcomponeitswere prcparcdby four methods: only two antiplretic,two antihistaminic andoneroticosteroid unfilteredpooledwhole blood-derivedplateletsin plasma; wen prescribedto patients, For the majoilty (64/68, or filtered pooledwhole blood-derivedplateletsin plasmai 94 lqo)ofth6etlansfusions,patientswercRotpRmedicated, unfilteredpooledwholeblood-derivedplateletsin plasma The activehaemovigilance programmedescribedhere trcatedwith ultEviolet B itluminationto reducehuman is a prospectiv€obsruational study,which was designrdro lzuc;rytcantigensensitization; plate- assessthe safetyprofile of PCT-PLTin routineclinical and frlteredapheresis letsin plasma.Noneoftbesecomponentswer<prepaRdwith practic€,Thedatafiom this prognmme represent tbe largest additivesolutions.The overallincidenceof ATR was 2.20lo prospectiveexperienceto date for r(ording potentialAE of transfusions,and 22oihof patientsexperiencedat leastone with platelettransfusions associated to priorstudies compared Afi. In comparisonto the TRAP trial, the cumnt study in of retrcspective designand limitFdin sizeIl0,l5-t81. The which all gradc ofreactionswrre rcported,both the propordon presentstudy was designedto b€ consistentwith Europear with a Raction was tower (0.70lo) ha€movigilance practices oftransfusionsassociated in whichreporting of all grad6 of aswell as the proponion of patients{2.8o,t') expeilencingat transfusion-associated reactionshas beer emphasized least one ATR.The useof 65% lntersol, a plateletadditive In contrast to otherhaemovigilance studies, obligatory {7,81. solution, in the prepaEtionof PCT-PLTmay partially conreportingfor all platelettransfusions wasrequired i[espectributeto the reductionin the obsewedinc'denceofATR Il 5]. tive ofwhetheror Iot an AE wasobserved, Thecurcnt study Theincidenc€ ofATRin thisstudycanbecompared to data focusedon AE that could be Iinkedto PCT-PLT transfusions frcm the haenovigtlancenetwork in France[7]. In France, afterstartjngtBnsfusioni buttherewerenospecificlinitations 322 J C Ossclaer`′ο′ prccestesforinactivationofleukocfesto 9 CorashL,LinL:Novel prevent trailsfusion-associatedgraft-vercu!-host disease.Borc Mdrrcu Troaplonl 2004; l3:l -7 10 Chambe6 LA, Kruskall MS, Pacini DO, Donovan LM: Febrile ractions aftey llatelet tansflslon: thr rffe(t, of single vsus nultiple donoN.Truntflsion 1990;3O12l9-221 11 Heddlr NM. KelmaL, Singei J, RichardsC, FedakP, WalkerI. Kelton JC: The role of the plasma ftom platelet concentratesin tGhstusion reactions:N Ergl J M€d 1994t lll1625-628 l2 MahganoMM, ChambersLA Kruslall MSr Linited emcacyof leukopoor pletelets for pwention of febrile transfuslon reacdo s. An J Ctiil PotholI99l ; 95:733-738 13 Heddle NM, Klama LN, ftiffith L, RobertsR, Shukla G, Kelton JG: A prospectiv. study to idertiry the risk factoE a$ociated illth acute r€actionsto platelet and red cell-transfusions,Iro6j6ion 1993:131794-797 14 Enright H: Facto6 influencing hoderate to severeieactions to PLI tansfusions: experienceof the TRAP nulticehter clinical dal, TruilsIusion2OO3 i 43 : | 545- | 552 15 Isola H, KienE D, Wicxl MI, Lafor.t M, Ohlnann P, Waller C, Mendel f, RaidotJP, Kandel G, CazenaveJP: Inplemcntation of photochenicsl inactlvation (INTERCEPT Blood Systen for pfatelets) in a rcgional blood center. Vo, Sang 2007; 9 3 ( Sl ) : I 6 5 1 0 2008 ThC Authorsl J o u r n t t cOonm pot a2● 0 6 0 B l a｀ ch kl wn 1g l L彼 Pt udS Ы "a ル “ “ j"1`12003)94,315-323 Haemovigilanceof photochemicsltreatedplatel.ts 323 16 Kerkhof-fsJH, Eikmboom JC, SchipperusMS, van WordngenVl.swinkel RJ, Brand R, Hawey MS, de Vries RR, BargeR, van RhsnenDJ, Brand A: A mutictnter nndohlzed study of the emcacyoftBnsfusiom wlth ptatelebstor€din platejetaddittve solution II veEus plasda, Blood ZOOGi108:32t0-lZt 5 17 dewildFEggen J, Nauta S, Schdjver JG, van Marujjk Kooy M, Bins M, van ProoijenHC: R€actionsand platel€t incrementsafter ' ftnsfusion of platelet concentrates in plasma or an additive solution: a prospective, Fndomized study. Iror.t!fusioa 20OO; 40:398-403 18 Heddle NM, Blajchman lrrlA.tvteyerRM, Lipron JH, Walker IR. Sher GD, Constantinj LA patteson B, Rob€rtsRS, Thorpe KE LevineMN; A randolnized controlled trjal conparing the frequencyof acute rcactjoN to. plasna-removedplateletsand prestorageWBc-reduced plateleb. Translusiofl.ZOO2:42t556566 ｍ∞ O 2008TheAuthods) Joumalcompilation @2008Blackwell Publishiigl.td., Vu Sangfinis l2oos)94,3t5-j23 PLICAT10NS Transfusion of platelet components prepared with photochemical pathogen inactivation treatment during a Chikungunyavirus epidemic in lle de La Rdunion Patrice Rasonglbs, Marie France AngeliniTibert, Phitip Simon, Caroline Currie, Herve Isola, DanietKientz,Marcstledts,Micrr;,a#T;::::J::;diu tartine in 2005, m epidemic of CNkunguya 1t-l virus (CHIKV) in the overseasFrench department \ oflledeLaRdunion,anislandintheSouthlndiil . I l:-f Ocem, resulted in the inJection of more thm one-third ofthe 750,000inhabitants by early 2006.rCHIKV is an enveloped single'strmded alpha virus from the Togaviridae family transmitted by Aed* mosquitoes. It genera.llycauses a mild febrile i.llnesscharacterized by arthralgiaslasting up to l0 days,but th€ recenl epidemic was associated wi$ myalgras, dematitis, hemorrhage, meningoencephalitis, respilatory failure, cudiovascular decompensation, and fulminant hepatitis with persistent anhralgias in somg patlents.'zSubsequently,more than 700 cases of CHIKV infection were reported in meuo-. politan France arnong returning travelers,and I infection ABBREVIATIONS: AE(s) = adverse wetrt(s); ATR(S)= acute tEnsfusion readion(s); CHIKV = Chikungun)" virus; CPA(6)= apheresis platelet component(s); CRF(s) = 6esg r.t.rt fom(6); EFS = f,tablissemeit Frangais du Sag; SAX(s)= severe adverse event(s); TT = tnnsfusion tresmitted. From the EFS IIe de La Rdunion Dd CHR Centre Hospitalier Ddpanemental Felix Guyon, St Denis, Ile de Ia Rdunion, after needle stick of a health care workerxl Owing to the high prevalence of CHIKV infection and the potentia.l for transfusion-transmitted (TT) infection, the Etablissement Frangais du Satrg (EFS lFrench Nationa] Trusfusion Servicel)suspendedblood donation on lle de La Rdunjon to prevent T"l-CHIIqIt To meet the requirem€nts for safe blood components on IIe de La R€union, red blood ceUs and plasma componerits (ftesh-frozen plasma) were supplied by EFS from metropolitan Frmce. Becauseof the limited shelf life (5 days) of platelet (PLT)components, EFS-La Rdunion' implemented pathogen inactivation prepilation ofapheresis PLI components (CPAS)to maintain local PtI component supplies.s Pdor researchstudies had demonstrated that CHIKV was inactivated by photochemical treauTent with amotosa.lenHCI and UVA light (INTER€EPT Blood Systemfor platelets, Cerus Euope BV Amelsfoort, The Netherlands).6 In addition, this system had been shom to inactivate high levels of a broad spectrum of viruses, bacteria, protozoa, md wNte blood cells (WBC) in PUf components.T's The INTERCEPTsystem receivedCE Mark regisuation as a Class III drug device and as of 2005 received approval ftom the Agence Franqaisede SdcuritC Sanitair'edes ProduiB de Santd (AFSSAPS, French Agency of Medical Safety of Health Products) for use with both apheresis-and.whole blood-derived PLI components in France.: The INTERCEPTBlood System Ms implemented in routini practice as ofVarch 13, 2006, by EFS-Uede La Rdunion. To date, approximately 4000 INTERCEPT-CPAS have been adminlstered to a broad range of patients on IIe de La Rdunion. After the fust year oi routine use of pathogen inactivation.to prepare PLI components, we conduct6d a retrospective analysis of the response to fiansfusion.of i95b componerits to determine the incidence of acute transfusion reactions iATfu) md serious adverseevents (SAES)attributed to use ofthis novel component, In addition, we determined the incidence of TT-CHIKVinfection fdr the nJst yeil after ifi plementation of pathogen inactivation treatment during the CHIKV epidemic. F!an@; CHRGroupe Hospitaller Sud Rduiotr de St Piere, Ile de b Rdunion, FBnce; CeiusCorporation, Concord, California; MATERIALS AND METHODS EFSAlsace, Strasboug, Frilce; Cerus Euope BV Ame6foon, The Netherlands; the Universlty ofCalifornia School ofMed! Colleclion of PLT.components cine, Sil Francisco, California; INSERM U.3l I and UniveGitd BeforeinEoduction ofthe INTERCEPTsystgm, CPAswere the sole tlpe of PtI component provided by FFS-La Rdunion. All CPAswqre couected in donor plsma with integral fi.luation leukoreduction (Haemonetics, Brainuee, MA). After introduction of TNTERCEPI,PLIS were collected in approiimately 407o donor plasma.and 60% PLI additive soluuon (Intersol, Fenwal, La Chaue, France) ftom donors with PII counts of 250 x 10'g/Lor morc using a blood component collection system (Haemonetlcs McS+ system\r;th the GSDPsoftware) to allow automatic Louis Pasteur, Strasbourg, Froce. Mdr6s reprint requesls loi Lauence Cordh, MD, Cerus Corporation, 241 I Stuwell Drive, Concord, CA 94520; €-mail: [email protected]. Thi6 studyw€ supponed in pilt by Cerus Corporation. Receiwd for publiBtion luly 28, 2008; rcvision received Decehber 12,2008, and accepted December 12,2008, dol l0.l ll l/J.1537-2995.2009.0211 l.x TRANSFUSION 2009;49:l0B3-1091. Vo ume 49.」une 2000 TRANSFuS:ON 1003 1084 TRANSFUSION Volume 49, Juns2009 addition of Intersol. The tilgeted PUf dose per collection was 4.0 x l0rr or greater.WBC contamination was reduced by fi.ltration with an integra.l WBC filter (Haemonetics). In addition to stmdad viral screening tests, donors were tested for CHIKV.infectiOn by an investigational reve$e.transcriptse polymerase chain reaction assay (RT-PCR).lro Psthogen Inactivation treatment of PLT components CPAScontaining 2.5x tor! to 6.0x l0rl PI-TSin 300 to 390 mL of approximhtely 40% plasma and 60% Intersol were prepared with pathogen inacti%tion using the INTERCEPI prccessing system (INT2202, Cerus Europe BV) acpordihg to malufacturer's instructions for use. Briefly,a unit of CPAwas mixed with amotosalen (nominal final concentration of 150 pmol/L) and illumlnated with long-wavelength ultraviolet IIVA (320.400m) light for a 3 J/cm?oeatment. The illuminated PLjI mixtue was incubated in a compound adsorpiiondevicein a temperature controlled PLT shaker/incubatot (22!2'C\ for 6 to 16 hous before $ansferring to the final slorage container Tleated CPASwere stored for up to 5 days under standard blood bank conditions before issue for transfusion. Hemovigilance surveillanca General study design Thls was a reEospbctive anglysis of data recorded prospectively in plimary care mefuca.lrecords and ai part of the AFSSAIS active hemovigilance surveillance program-rr There were no patlent inclusion or exclusion cr! teda other than the requirement for PLT transfusion. All patients who received PLI transfusion support during the dehned-study period were included in the analysis. Case report forms (CRFS)were used to collect patient datar2on each transfusion of INTERCEPT-CPAsbetween March 13, 2006, and March 13, 2007, regardlessof whether a adverseevent (AE) was reported The prindry endpoint of the study was the propor. tion of transfusidns with AIR after administration of PLI components. ATRSwere defined as AEs possibly related, probably related, or related to a PUI $msfusion. SAES were defined as AEs that were fatal, life-threatening, or disabling; resulted in or prolonged hospitalization or morbidity; or were incapacitating. Secondary endpoints included evidence of acute TT-CHIKV infecdon (basedon nucleic acid mplification of viral sequences).All transfused patients were monitored for 7 days after each trans. fusion for potential TT-CHIKV infection using standard EFS operating procedures,roData also were collected on use of INTERCEPT-CPAS by patient priniary diagnosiscategory md clinical indi€tion fo! tlansfusion. ヾ∞ BACKGROUND:Duringthe Chikungunyavirus (CHIKV)epidemlcon ll€ de La R6union,France,more than 30o/oof 750,000inhabitantsw6r6 Inlected.Local blood donallonwas suspendedlo prevenl lransfusiontransmittedInf@tion(fT.CH|KV). To suglalnlhe avail abitdyol plat€tEt(PLT)components,the Elabli$emenl FEngdis du Sang implsmentedunlversalpathogen inactivalion(INTERCEPT,Cerus Europ€ BV) ol PLT components(CPAs).The study ass€ssedthe Eafetyot PLT componenlstrealedwlth pathogen inactivation transtussdIn rcutln€cllnlcalpractlce. STUDY DESIGNAND METHODS:This was a retrospectiveobssrvallonalstudy using palient medical recordsand th€ AFSSAPShemovigilancedatabase (€FlT) to ldenllfyTT-CHIKVand advers€ evenis (AEs) dlasifigd as adte tansfsion raactians(ATRS)to PLT componenlspreparedwlih pathogen Inaclivation. RESULTSi Durlng1 year, l95O INTERCEPT-CPAS wore lEnsfusEdto 335 adutt, 51 pediatric,and 41 intanl patlenls.Ninets€nAEs were obserued in 15 patienls and l0 weF.classitiedas ATRS.Eight.ATRs@ured in palients.No ATRS 6 p€dlatdchematology'oncology were obsgruedin infants,Ths most frequentlyreported slgns and symptomsw6re Gmde 1 urticaria,itching, chllls,tgver, and anxlely.No cas€s of transtusion" relal€d acute lung InJuryfi-s€psis, or TT-CHIKVw6ra d€lectod. were well tolerCONCLUSIONS;INTERCEPT-CPAs al6d in a broad rangeof patients,IncludingInfants.ATR Incldenc€was low and when presontATRSwero of mild s€v6rity. LiIy Lin, Laurence corash;and RASONCLES ET AL. PATHOGEN:NACTIVAT:ON AND CHIKUNGUNVA ViRuS same criteria as used by the AFSSAPS.hemovigilance system.ll The standardized CRFshad been validated in a prior hemovigilance study.-hData from the CRF were entered into an independent electronic database used for postmarketing hemovigilance prdgransrz rl and reviewed by the principal investigator for incomplete data. At the conclusion otthe study,AEsclassifiedas transfusion leactions based on review ofthe primary cae medica.lrecords were compared againstAEsprevioNly repotted under the AFSSAPShemovigilarce progmm recorded in the eFIT databasetrtodeterminerhe rotal incidenceofAls attributed to PLT tnnsfusion, These data were then ana.llzed to determine the incidenceof ATRs. Statistioal analyses A statistica.l analysis plan for the study was prepared and approved before analysis. All statistical malyses, summary tables, and data listings were generated using computer software (SAS,Version 8.2, SASInsritute, Cary NC). The primary assessment was the incidence of transfusion reactions.The number and proportion (%) of transfusions ed the proponion of patients with one or more transfusion reacdons were summaized overall,.by seriousnessmd by relationship to PIT transfusion. Corre-r sponding 95% confidence interuals (CIs) for the binonial proportion were calculated uiing the F distributidn method. The 957oCI were based bn number of Datients with my A-E/ATRand the number of tansfusions aisociated with ilyAE/ATR. In addition, the patient population profi.le,the charaderisticsof the PLI components,and the chamcteristics of the AEs after PLT transfusion were analyzed. Analysesto identii/ risk factors potentially associated with tansfusion reactions were conducted using multivariate.logistic regressionanalysis md by assessing association at a 10%significancelevel. Data were malyzed on a per-transfuslon and a per-patient basis.NI.INTEhCEPTPLTcomponents administered to patients wele part of the full analysispopuJationandwere mallzed, whether_ or not an A.Ewas observed.All ana.lyseswere conducted using this firlt malysis population. PLTcomponent characteristlcs Each CPA was teated with pathogen inactivation using the INTERCEPTBlood System on either Day 0 or Day 1 after Pijf collection and stored for up to S days before release for uansfusiofu PLT components were released after completion ofserologic and NAL PathoganinactivaUon treatment was used without bacteria detection other dran routine quality control (QC) assays.pathogen inactivation treatment replaced cytomefaloyirus (CIvfV) Vol● m● 49,」une 2009 TRANSFuS:ON 1085 uansplantation, Among the pediatric datient group, the proportion of hematology-oncology patjents (66.7%)was significmtly higher 1p=9,9911 than among the adult patient group (26.3%). Approximatelyhalf of rhe patient population (5l.5yo) rec€ived [ansfusions in intensive carc units and the other half (48.sqo)weretmnsfused on non-intensive care hospital services (Table l), There were no outpatient transfusions in the current sweiuance program. Subgroup analyris showed that, while most ofthe pediatrjc patients (78.4%) were transfused in non-jntensive care.hospital wards, the majority ofinfanb (9O.2qo) wele transfused on intensive care units. Patient demographlcs PLT transtusion exposure Alproximately 53% of patients had a prior history of transfusion exposure to some blood componenl The median number of PLI transfusions per patient was 2.0 (range, l-66; Table2). Of 1950 PLT uansfusions, 1372 uilsfusions were administered to adult patients while 487 and 9l tnnsfusions were administered to pediatric patients ild infants, respecrively.Based on the respective patient population, 36 to 47Voof patients received two or more PLT transfusions. The number of tnnsfusions per pedjatric patjent (9.51 14.7)was significantly higher (p < 0.001)comparedto those ln the adutt popu-f lation (4.1 a 6.2) while rhe opposite was true for infantsw (2.2t2.4, p <0.002). Based on primary diagnosis category, hematology.oncology patients in all age groups received a higher proportion of PLI. tramfusions per patient than drose in other diagnosis gloups (Table2). Between March 13, 2006, and March 13, 2007, a total of 1950 INTERCEPT-CPAS were Emsfused to 427 patibnts (TableI). Each patient received at least one INTEnCEPTCPA. The patient population consisted of 335 adult patients (>18 years), 5l pediatric padents (>l to <18 yeats), and 4l infants (<l yea). There were more nale patients in each age group (Table l). Hematology-oncologydisorders treated with chemtherapy and stem c€ll transplantation constituted 29.0% of the primary diagnoses among the trilsfused patient population and these paUents received 6l% of the pllf components (lhbles I and 2). The largest patient group supported with PLI components w6 rhe generalmedical population (58.5%),but they receivedonly 30% of the pLT components. A number of patients receiving pLI uansfusions (12.2%) underwent major surgiial procedues including cadiovascular surgery or solid organ l TABLE l:pem。9[lphi● S 。[2,tients trantfus,d with:NTERCIPT・ cPA3' Podl●lc(￨・ 50 _`duに (n.335) Mal€ Female Aga (y€ars) M6an i SD Median Flange Car€ location lnlgnsivo Nonintensiv6 Homatology-oncology primary th6rapy Convontionalqhemotherapy Slen c€ll transplant Surgery Cardiovasculaf Solid ofgao trangplat Gen€rsl m€di€l 262(614) 165(386) 460 (l to 87 220(515) 207(485) 124キ(290) 107(822) 14(113) 52(122) 49(942) 3(58) 250(585) 2021603) 133(397) 9 4 ±5 3 >181087 172(5'3) 16314871 87(2Q3) 69(793) 10(115) 48(143) 45(038) 3(62) 199(5941 1(0.3) The number of pEtignts(n) and th€ proportjon(%) within each €tego.y pe"nfeo. "rJ i Ag€ for infantsWasonly .@rded Es <1 y6ar NA = not applicablg. t Eight aduh paltafs had no activs thorepy sp@ingd at ting ot transiugion, 1036 TRANSFuS10N Volum● 40.」Ⅲ 02009 o5(686) 16(31.4) l t0 18 ４ 。 ４ ３ ３ ０ ４ ０ １ “ ３ ３ ︲ RESULTS serology for patlents who required CMV-safe PLTSand replacedgamma irradiation for prevendon oftrilsfusionassociatedgraft versus hos( disease, The INTERCEPTprocess resulted in a mean PLI loss of 7.8%dUeto volume loss duing container trmsfers. The mean PLI yield of INTERCEPT-CPAS was 4.Zxt1tt ! 0.7 x l0rr Plfs per component. The residual WBC count met the national .QC requiremeni (<0.5x 106/unit). Approximately i5% ofPLT components were divided into 2 units befote tiansfusion to fulfill clinical demand. The proponion of split PLI components was similar to that in the period before inplementation of pathogen inactivation. 的 問 回 ｍ 囲 田 ｍ に Ｏ Data collection methads All patients transfused with PLfs prepared by EFS.La RCunion ftom March 13, 2006, through March t3, 2007, were identi.ned from the EFS-k iidunion electronic database for the collection, production, and issuance ofblood components. Each patient was identified with a unique study number to preserve anonlrnity The following data were collected; PLT product code; patient unique identifi, cation number associated with the component, patient 'demographics (age, sex), and primary diagnosis based on clinical care area; primary therapy (chemotherapy, hematopoietic stem cell transplant); surgery (cardiovascular or organ trmsplant); or other (general medjcal or multisystem organ failure). Primary cile medical records of each patient were reviewed for the 24 hour period before each uansfusion to establish a baseline profi.le of the patient's clinical cond! tion, for 7 days after each PLT trmsfusion to idenrify new AEs arising after transfusion, and to record the relationship of AEs to PUf tnnsfusion in the prirnary medical record as assessedby primary care ph,Ticims. This review was conducted by an observer without knowledge ofAIs reponed in the AISSAPS hemovigilance system (eFIT).rr For the 24 hours before and for the 7 days after each PLI transfusion, medical records were specifically reviewed for widence ofclinical conditions that couldbe attributed to transfusion-related reactions, including fever (increase in temperature of2 or l'C with chius), chills, nausea,skin rash, urticaria, dyspnea, bronchospasm, tachycadia or bndycardia (change in heart rate by >25 bpm), h!?otensiod or hypertension (decrece or increase in systolic or diastolic blood pressure >30 mm Hg, respectively),hemoglobinuria, hemolysis, and change in general well-being. Specific criteria were prwided. for the diagnosis of transfusion-associated acute lung injury (TMLI).!3 Clin! cal microbiblogy laboratory records were rerliewed for documentation of trmsfusion-csociated sepsis, The diagnosisof uansfusion.associatedsepsls required.the isolation ofthesarnebacteria speciesfrom the patien! and the implicated PLT component. Tlansfusion CRFswere completed for each PLf ransfusion regcdless ofwheiher or not an AE was noted in the medical record. In case of the occurrence of an A!, add.itional clinical and biologic information as well as test resu.lts for CHIKV infectlon (nucleic acid resting (NATI by RT-PCR)were collected. These data were used by the medical record reviewer for assessmentof causa.lityand swerity based on the medical record. Clinical severity of AEs was classified according to the following scale: Grade 0=isolated dysfunction without clinica.l or biotogic manifestation; Grade I = absence of inmediate or longterm life-threatening effects; Grade 2=long-term lifethreatening effects; Grade 3 = immediate life-tfueatening efrectsiand Grade 4 = death. The relationship ofAEs to the mos! ploximate PLI transfusion was classified using ihe RASONGLES ET AL. 1nlants(n=41) 25(610) 16(390) NAI NA十 37(902) 4(98) 0(73) 3(1001 0(0) 1(24) 1(100) 0(0) 37(003) PATHOGEN INACTiVAT:ON AND CH:KUNGUNVA V:Rus TiBLE 2, Trsnstusion sxposur3 among pa$ent populsilons A‖ All palients Transfusions(n) Mean i SD M€dian Rangg H€malology€ncology Transtusions(n) Mean l SD lredian Rang€ Surgi€l Translusions (n) M6an a SO Median Range General medical Transtusions (n) M6an : SD Medlan Rilg€ Mlssing diagno$s Translugions(n) Mea : SD M€dlan Range patonts(n=427) ６ 。 ６ 帥 け ． ２ ︲ Popuatbn 6nts(n=335) Adun pa‖ Pediatrc lathnts(n=51) h●nt pa‖ ono(n・41) 60 ０ ︲ ６ ¨ “ “ ︺ ｏ ・ フ ︲ ︲ 135 28■37 20 24=28 ３は﹁︲ ３ ︲ ３ ３ ︲﹂御︲ 4(09) 5(12) 5(121 S(121 1(02) 4(09) 1(02) 2 (05) 4(09) 4(0.9) 2(06) 4(12) 1(03) 1(03) 1(03) 2(06) 9076) 13(27) 0(113) 8(16) l103) 210、 6) 0 2(39) 1(20) 4(78) 4(78) 0 4(78) 4(78) Anメlety 2(39) Othe1 6● 41 2105) 1′ 2(39) 103, 0 5(98' ' Oata are roporled as number (%). No AEs w€r€ reported for infant pationts;lhus, these palients and transfugionsare not includ€din this t8ble. t Numb€r ol signs/symploms can qcegd numbgr ot AEs du€ to mulllpl€obs€ruedsigns/symptgmgper AE. relationshiplhat an AE was possibly r€lated,probably relaled, or relalgd lo INTERCEPT-CPAlEnslusion. ATR = EHI AE6 and ATR8 atter PLT transfuslon The incidences ofAEs and ATRSwere evaluated on a pertransfusion m well as per-patient basis fTable 3). On a per-transfusion basis, 19 transfusions (9570 CI, 1.0%. 1.5%) were associated with m AE. Of these AEs, l0 (95% Cl:0.580-0,9%)were clasified as ATRSpossibly, probably, or related to INTERCEPT.CPA$ansfusion. No SAEs,no 1;P」 侶 ぽ η tered hematology-oncology teated potentially immune-suppressive therapy, There were ho cass of TICHIKV reported in thjs suruey based on the test results using an invstigatlonal a$ay for vhal hucleic acid or posttransfusion clinical obsermtion. for signs aird slmptdms of CHIKV infectjDn. casesofTT-sepsis, no casesofTRAII, and no deaths due to INTERCEPT-CPAtransfusions. were reponed. On a per-padenrbasis, 15 patibnts (95% CI, 3.5%-5.7%)wio leceived at least one trarsfusion of INTERCEPT-CPAs experienced an AE after PLI transfusions (Table3)i Only 8 patients (957o CI,1.9%-3.6%) experienced an ATR attributed to INTERCEPT-CPA trusfusion (Table3). Vol●n●49,」une 2009 TRANSFuSЮ N lo87 '嵐 ′ 蜜 鑑 聴 謝譜 ∬出雷 躍 1島 patent basls Most of ATRs we,described as Grade l itthmg(00%),品 carla lo,9%),ald Ch」 Is(o5%)● dl all bhe■ ObServedat a rate Of0 2%orleSs per patient. fA「 s an,AT,6TP'製 itri: :li:11° 161'S° . DtscusstoN CHIKV resu.ltedin an epidemic on La Rdunion Island iri which appro:timately4l% of the population was infecied. Serologic and epidemio)ogjc suryeillance studies estiPё d●tiC'atlents expenenced a hlghOr mtidencl of AEs mated the preva.lenceofasymptotnatic infectibn at t5% of total CHIKV infections.' Efforts to identiry infected blood 甘 耀 じ謬 器 鞘 11踏 :1織 糊 :』:凛 dono$ ltith either serologic assays or CHIKV specnc patents compared to l AEs 10 4%)an1 2 ATRs(0:1%)1, nucleic acid amplification assayshave sholvn consideradut pauen“ c Patien“ onaper_patientbasis,9 pedia● able variability and suboptimal sensitivity.r5Themean,risk 0767)exP,nOncod at least ompared l AEし to 6 adut ofcontamination ofa blood donationthroughoutthe epipatents o 8701 Smlarly 6 pediatlc nts(110%) Patё demic was estiinatedat 132per l00,000.donations, md at e,periehced leaSt a、 l ATR,omp● ed t0 2 addt,atelts the peak of the epidemic, the risk was estiinated at l,500 (06%) per lO0,OOO donations.r At the time of the current study, For aE.AES repb=“ d in pediatrit patents, the optimal methods to detect infected donors with low.viral Sッ mptOpsysigns were prё dbminandy Grade l m sever, titer6.werenot available, and a NAT with sensitivities of 40 conSsl●g offeve■ chls,itclung,ur"ana,aぃ。e,tachI to 350 copies/mLwas only developedlater.roIn.the period cardla,and●lala.slhg‐Cable p)For pediatric PaJβ nお of this study, collection of CHlKV-contaminated PLTS expert,chgダ Rs● 9 spOptOms/dglヽ hduded ichm3 ftom asymptomatic donors was plausible. Driringthe epiurticaria,tachycardla,and facial nushhgi none of which demic before w€ of pathogen inactivation, two casesot were r■o●ё d h admt patients NO AEs wett associated TT-CHIKVwere suspected,but neither casecould be conwiththe 91 NTERCEPT‐CPA transmsions admmstered to clusivelyproven.'0At leastone blood-borneuansmission 41■nfants who requlred PLT su,pOrt due to a needle-stick has been documented.i This study accomplished muJtiple objectives. ForeCh●ractOFlstics Of AEs and ATR3 aSSOCiated unth most, it provided hemovigilance data to evaluate the transfusion of 3p‖ t cOmponents efectiveness of the INTERCEPTBlood System to prevent Of the 1950 tran,Fusions,540 1NTERCEPr CDヽs、vere PLT TI-CHIKV durin! an epidemic. These data are espeobtal,edfrOmlspl■PLTcomp6nent The ratoS OfttESand cially relevant given the specificassociationofCHlKVwith 1000 TRANSFuS'ON V● l響 uno 2009 "。49,」 ０∞ 1 ( ●1 ) 2(01) ￨(0:2) 0(03) 0 0 2(01) Pedjavic pati€nts(n = 51) Transtu$ions{n = 487) ０ ０ ０ 5(03) 7104) 5(03) 7(04) 1(く01) 4(02) 0(03) ωｍ ｕｏ 10(05) ∼口t patlens(n_335) Trans,siOnS(n=1072) 問ｍ ｍｍｕ鰤ｕｍ団 TranEfusionswllh I or >AE Sign€/symptomspgr tBNlusiont FeVer Chill● Itching urtlcana Dyspnea Anxl●ν Olいo「 Signs/symptoms per pa“entt Fover Ch‖ls ltching Uttcatta 1 5 ●5 ) 19(101 fl: 品 l棚n=鶏 鶏器 蹴覇轟』 :場 首 ツ輩:踏 d a l s y m p t o m s h t h e octahteerg"olrnyd iodfe“ ^ d d iO ● TABLE 3, Cllnlcal char.cterlstlcs of AEs and ATRSamonO pailenl populations. wi崎 lo子 1繁 E OVera‖patlent po,u:atiOn: BL二 l comp♀ °n l h e f r e q u T , y o f , E s a l d CharaCter:st:OS of c:lnica:sign3 1.EIect olザ 摯 躍ぽ 6iat,d With and sympto“s ass● PLT transfusicn Of au AEs, 9■ l perrtran,fuSOn basls,the host iOquently Observed TOla 1950 19 0 0) 10(05) Dala ar€ rcpgrledas number (%), ツnptoms/signs,3%104%of 19,Q tanSヽSiOns)were fevOL Is,itchingi ch」 and urticaria(Table強3).を ety(o2%) w a s t h e s , c o n d m o s t f r e l u e n t l y r e p osrllgend s yAIRS l n pon t oamper-transfusion ′ basisfor split components were l y o n e m c iO df e ■ O■ d y s p n e a w a s r e , o r t e d : 0.4 A d dmd i t090, i o nrespectively, al compiled to I:2 and 0.790for symptomsin■e category otherlincluded taChycardla,whole cdmponents. Of the 19 AEs reponed, only 2 AEs of“ hciai nushm3 b9dy Pain,ahd COЧ gh,lbⅢwith lh ind「 (one in a 77.year-old male patient and one in a l6:ye81%Or less of transfugons Most of old male patient) were associatedwith tmnsfusion of a ■dual mollente。 10・ (Table4). the ATRs were described prhcipally as Grade l wtcaria split INTERCEPT-CPAS di(Clulg(177)● th」i。 (her sylnp19mS/S`rS (03%)a■ observed at a rate of O l%o,less Of transhsions on a per‐ ed obseⅣ patent basis.the most frequcntly Incldence of TT-CHIKV symptO●s/signs(1.2700f427 en“ pa」 )were CHlls,itchln3 A substantia.l proportion of transfusions were adminis直ety lol,%)were tle ,nd uructtia(Table 3).Fever and山 to parients with 淵1鵬 瀾諄♀ hs 20 ・427) 測l pa1lonts● RASONGLES ET AL. PATHOGEN lNACTiVAT10N AND CH:KUNGUNVA V:RuS after transfusion of INTERCEPT-CPAS. This finding may not be surprising becausetIe proportion ofhematologyoncology patients and the levels of PLT component exposure were higher mong pediatric patients. On the other hmd, no AIs or AIRs were observed in infants who received INTERCEPT-CPA transfusions largely for nomalignant medical disorders, but this population was of limited size and less intensively transfused. The study also provided expedence with the implementation and operational logistics of the INTERCEPT system in a remote, small regionil blood center EFS-Ilede La RCunion performs approximately 100to 150 apheresis PLf couections per month.a Complete conversion to pathogeninactivarionofPLTcomponentswasachievedin 2 week. In routine operation, no additional personnel were required after implementation of the INTERCEPT sys(em. This ia $e fust study to demonstrate the utilty of pathogen inactfuadon as a proactive approach to prevent a potentially TT infection duirg m epidemic. The technology facilitated the availability ol PLT components that otherwise were in limited supply. This expedence is relevant given the obseryation of imported cases of CHIKV infection . in metropolitan France, Germany, the United Kingdom, BelSium, Noruay, the Czech Republic, Canada, and the United States32asand the aulochtlonous outbreal of CHIK infection in the EmiliaRomagna region of ltaly.26The successof EFS-ln RCunion in inplementing the INTERCEPTBlood System demon. suates the utility of pathogen inactivation to support the availability of labile blood compondnts during an epidemic. ACKNOWLEDGMENTS The authoF alEgratefulfor the supportofCh@talWallerin prq: viding guidanceed traiDingfor tbe cotrductof the hemovigilance study of pathogen-inactivated PLI components,Lynerte Sawyerperiormedcritical studiesto validateinactivationof CHIKVinPLf andplasmacomponents, Theauthorstha[k Carole Ripaudfor assistucein facilitatingcomunicarions betweenthe inwstigators of EFSL€ Rduion and CerusCorpontion and Hmoverfor editolialassistance Wea.lsoacknowledge Jessica the effortsoftunaud Besnddih facilitatingthis study. CONFLICTOF INTEREST Threeauthors(DS,[.I. andrc) werea!frliatedwithild heldstock or stockoptionsin CerusCorporationduringthe cotrductotthis study.M, wd a @nsultantto CerusCorporation, md CCreceived a rsearch glilt &om CerusEuropeBVfor cotrductof this study. JPCreceivedresesch6upported seryesoo ScientificAdviso.y Boardsfor Ceru6CrrpoBtion. Volume 49.」une 2000 TRANSFuS:ON 1039 : ve obsewa● A prospec● Ond cohort saFew study oF5106 ul 1hteやt transFuSons uslng components prelared面 photOchemlⅢ p a t h O g e n i n a c t l v a t o n t■a F enaⅢ= tme、 REFERENCES l Brouard Ci BOFrttOn P,Quatrosous I,P,uonel l,AsalA,Dさ Valk H,Desendos,C,WorkゴOu,″Quan,tative ESthatibn o f ●e R I s k o f B 1 9 9 d P O n a d O n c o n tn aりm lInnaゃ お 01S ct ● 71 sion 2008148:1061・ 13.iernard GR,Artigas A,3ngham KL The Amencan_ AgentS",stⅢated isk of a,た “″ "おb160d EuropOan Consensus ConferёnCe on ARDS:demioons, "ayaレ:″ donatloFl dWhg。 Ⅲ mecllankms,relevant out"mOs,and cu1lical trial coordi‐ nldand h me ,demiC On Reullお lndian ocean,2005 to 2007 Trans■ nation Am J ROsp,Clt care Med 1994:149:81842 slon 200848:1333‐ 41 2 Schlltenecker:,Iteman l,Michault A,MuriS,PrOngeul●14 0sselacr JC,Cazenave,P,Lambし rmont M,Garradd o, ヽ ア ぃ。 Hidalat M,3arboua L,Tard市 F, V dler c, el R,DeFom Lヽ yMc,Lavent R,Pardlgon N,RepesIM,Pettind‖ Mendd I,Rttdot IP,Kandd C,DeveuteFR,Pablgi Dehenau D,Ar,oyo IL,Padr6n P,Goue7ec Hi Corral M, Bヽcornet L,Diancottt L,Micle1 0,DuquerrOy s,Culgon C, Frenklel MP,BrChn AC,Cubito N,Despや sP,KunsI F,Rey FA,Zeuer H,lnSSo S.GenO●e mooe,du● on 6f Chlkun‐ gunva宙 ruses caushg the lndlan Ocean outbreak PLoS Med 2006:3:1‐16.. P, Iacquct M,Sundin D,Lin L Cor■ h L m aCtive haemovlgl‐ lancO progrmme charに te●ang the sarety pFOhc o'7137 ' Platelet transfu,Ion,Prpared哺 ふ a“o,osalen phot。 ‐ chemcaltreatment Vox Sang 2008,94:315,23. 3(asunOva E,QuateSOus',TarantOla A lmported cascs of Chkungunya h me"pOHtan Fran":update lo June 2006 15 Manよ eOD,Niedrtg M,ENIVD Laboratory capacity for Bュo Surv01 200011:“ 60821‐ 060324 detecuon of chlkungunya w輛ュ l hFectlons ln Europe 4 CordeI H,QuaOSOus L Paquet c,CouturiOr E Imported Euro SЧrvein 2007:12 Avauable tom:http:″ wⅧ “ cases of Chlhnguny■ eurosuⅣemanclorg′ew′2007/070913 as夕2 Ap●12005・ l metrOpoutan Franc● aw,906,Ewosu“ 恥br● Ш209,111EOo0420 060413 5 Rasongles P,IS●aH,KientZ D,Cazenave JP,Sa″ γer L Corash L Rapid Ⅲplementalon oFphOtochemtal patho‐ gen ina■ivatiOn(DITttCEPT)● =preparation of,latelet COrnP。lentS dWlng an epidemlc of Chikungun黎 ¨ru, Vox Sang 209o,916upp13):32 6 SavwerL S,mp"n.JOlanneS A,Dubens● T,KhscyJ, Tsetsar01 K Vmandlngham DI早 iggS S Inactlva● o,of 16 Lawent P,Lc Roux K,Cr市 ard P,Berttt G,Naze F,Picard M, stattsky F,3arau C,SchttneckeFI,Mthau■ ^DO“ 1・ opment 9fa sCnsitlve real.tⅢ O臀 VerSe transclptase PCR assay● t h a n i n l e r n d lCtOon tlゃe t e c t a n d q u a n t i ″ chikungunya ntus Clln Chem 2007:53:1408‐14 1 7 C h e r n e s k y LMa、 rke RP Contras,ng ereOs oFlabblt huⅢ a n p l a t d chtksu nOgIu nCy・ nal宙 sふ fectM,c贔 , ヽlicrob'ol 1977,23:1237‐ 44 c h i t t n n" -n 3ッ1 n p l●薇 e t s " d P l a s m a u s n g t h lS e I卜 町ERCEPT 31ood Systemtt Sang 170支200793(suppl l):170 7 11n L,Dlkeman R,Moll● lB,Lukehart sA,Lane R,Dupuヽ K,Mc● el P,Corash L Photochemlcal treltment of platelet concentrates●th amotosden and Wヽ hactivates a b=oad 卜∞ Pl;fs,rzrowhich could lead to low detection sensitivity for serum-based tests,In addition to evaluatingthe efficacyto prevent TT-CHIKV this study provided an opportunity to entend the safety profile of INTERCEPTPLIS tmnsfused to a broad patient population. Finally, this study permitted an evaluation of the operational logistics of the INTERCEPT PLI System implemented under emergency conditions. Data provided by EFS-[.aRCunion for the yeus 2dO4 md 2005 with conventional PLI components suspended in 100% plasma indicated m'AlR incidence of 2.2 and 5.4% of PLT transfusions among heavily transfuied pediatdc oncology-hematology patients, respectively.reIn comparison, this study demonstrated a lower incidence (1.6%)ofATBs per PUI fansfusion. These results are consistent with reported ATR frequencies reported for INTERCEPTPUI components in routine use from multiple European centers,rar' but lower thm the frequencies reported for treated PUI components in the Ewosprite (6%) and the SPRINT clinical trials (3%).20"The higher incidence ofAIRs observed in the clinical trials may have been due to differ€nces in padent popula$ons, which in the clinical trials consisted largely of heavily transfused hematology' oncology patients undergoing hematopoiedc stem cell transplantation. Similar to previous studies, all of the ATRs observed in the curent survey were of mild severity, and none wer€ indicative of clinical CHIKV It is relevmt to note that the size ofthis studywas insutficient to characterize the incidence of septic trmsfusion reactions, although none were reported. The clinical symptoms of CHIKV infection include fever, swere polyanhalgia, myalgia, dermatitis, hemorrhage, meningoeniephalitis, respimtory failure, cardiovascu.lu decompensation, and fulminant hepatids with a monality ratb of one in 1000 during the La R€union epidemic.22Thus, review of pdmary medical records should have been suhciendy sensitive ro detect TT-CHIKV No TT-CHIKV caseswere detected in the patient population monitored in this study after implementation of the INTERCEPTBlood System for PLIs. The retrospective suveillance described in this repon provided an opponunity to evalua(ethe sensitiviry of the AFSSAPSactive hemovigilmce systemrr to d€tect trmfusion-relatad AEs.We did nol detect any additional uansfusion-related AEs in our independent review of primary medical records compared to the AFSSAPS/eFIT database for transfusion-related incidents. This limited experience is @nsistent with the sensitivity of the AISSAPShemovigi.lancesystem in detecting transfusionrelated AEs. This study included a substantia.lnumber of pediatric patients, some of whom were inJmu. None of the prior studies with INTERCEPTPLT components included a substantial infant patient population. Interestingly, pediatric patients had the highGt raie of AEs and AlRs RASONCLES ET AL. Larke v,hthedoⅢ EF StabnレanOn oFchikungunya宙 rus i,Fec● ●ty by human bloOd platelets I Infect Dls 1970,1221 523‐ 31 19 Angelinl‐Tibert MF,Rasongles P Into■ ra,Ce des CPA traltes p● INTERcEPr― Amotosalen e,o■ co pediatrie paris;Etab:issement Francais du Sang;2007 spectrum ofpa■ ogenc bactoHa TransFu`lon ;20041“ 20 van Rhenen D J,Cu:llkSsbn H,Cazenave IP′ Pamphuo,D, 1496‐ 504 LlungFan P,Kluter H,Ⅵ rme,H,Kappers_Klume M,do Creef GI LaFore,M,Lioure B,Da■sK,Marbhe S,Mayau‐ 8 Ll,L,Hanson CV Alter HL Jau、 哺 V Bcrnard KA,Mwthv KKI Metzel P,cOrasl llnaltiVa● o,of、Ⅲvses in platdet don v FI徊 lentI,conla,M,Lin L,Metlel P,buChh91z D, concentrateo by phot9chemtaltrealment“ ぬ ¨001os」en Corash Li euroSPRITE t● ali nanshslon oF pooled bu町 aFld 10,g‐ Wavel"gth u● 。 let hght■ SOn 2005■ coat platelcl,o,pOnents prepared witt phOtOchemical a“ anS｀ , 58000 ent the ewOSP路 ■ trial patl10gcn hactivation treatお 9 Castro E,Ctrcnes N,Bueno JLi CarJOn,,L● Blood 2003i101:2426‐ L,Fresno M 33 T h e c m c a c y o f l b o t O C h et,elaCt」 r n e n t t t t h a meOnt o s 」 21 McC口 lough,,%sole DH,Beniamin RI,SlichteF S',PIneda HQ ahav、 ぃ●。let A Nα 「ERCEPT)お r lnactivation oF rry・ A,Snyder E,Stadtmauer EA,Lopez‐3aza I,Coutre s, ‐ ″`σ烈7'mp● 。led bu″ oOat platelets Transhsioh S t F a u S S R C , C o o d n b u g h L T , F r i d e y JeL ,lR,a l i e t C a Ы ′αえὸο Murphy S,H… ard F 4th,Davis K,Lul JS,MOtzel P,C● 2 0 0 7 , 4 7 :4413 4 ・ rash 1 0 ハi g e u r u M F , F _ y P , R a s o n J e S P E p i d ` m ig cu ・d e c h i Li k u Koutsoukos ■ A:Lm L,Blchholz DH,Conlan MG TheFa‐ nya l hvmoh Rё et rans,s10n Sanguhe■ ■ e Buuetln de th a photo‐ peuac ofFlcacy and saFeυ oF platelets treated哺 r■￨口 。 0● 139・ Chenuc」 prOcess for p。 10 ふogen“ aCtiVation:the SPRINT ●gi攣"dしl AFssaps却 1l Anl"uG,MoraR Ⅲ oIF,RObbO D′ ´h宙er C,Hl¨ 1lal,100d200,,104:153441.( ⅢⅢ P,Hemttigtance ne■ voェ 22 Renaut P,sOlet,L SISSOkb D A maloF epidemiじ oFchinⅢ ト“ nanc。 。18管i“■OFl and anal"lsoFhmeⅢ te tansh`:on incide,treports iOm mya vLuslnfeclon on Reun10,Island,France,2005, 1994‐ 1998 hnsmslon 2002:42:1356‐64= 2006仲 J nop Med Hyg2007,77:727・ 31 12 0,selaer IC,Mess9 N,HerVlg T,Bueio J,caStro E,Espl‐ 23. AngeuⅢ ・ Tllert ME Currie CI Slaelts M,C● rasl LM, nosa A,AccprsI P,Junge K,,acquet M.FlamentJ,cOraぬ L 1090 TRANSFus:ON Voluho 49,」 une 2∞9 RasOndeS P SattyOfplatdet cOmpOnents prepared“ th and PATHOGEN:NACTiVAT:ON ANO CH:KONGUNVA VIRuS :ξ 胤iよ よ T忠lLp眈 憮 棚鮮I淵 ばli罵 鍵l搬席協 織 T編]熾1闇 4322A MOrtalヽ Vtty Rep 200● 5511040‐ 2 ‐ 2 4 D e p O O r e r ce o■u l o m b i e F Du nCgh“ yよa r i s k a s s e 2s 6s ‐R e z z a C , N I c o l e t t i L , A n g e l i n i R , R o m i R , F i n a r e n l A C , :話 『 器=籍‰ 1器 よ 調現 T脳」 酪 譜茫 ,ll鷹 ぶ「 1ビ' 議縁 凝鷺瑞 eurosu晋 1lanCe oFg′ eW′200,′ 2 cassonO A CHlKV stud,group lnた c●On輛 th chょun証 ‐ "051l asp″ er E,Carcね・ Di″ J,B」samO G,Shranatan S,3erg_ nya urus in ltaly:a16utbrak ln a temperatよ e」。i 15.Lr● Blauwet t,sohan M,Baddoじ L,Reed C,Baggett Lancet 200■ 3701840‐6ロ ,annへ H′Campbeu cr smith■ Powersん Hayes N,Noga A′ ∞∞ Volurne 49,」 une 2009 TRANSFuS:ON、 lo91 後調査及び観察研究の TRANSFUS10N PRAOT10E ROUTINE uSE OF PATHOCEN INACTIVATED PLT COMPONENTS Univers4 adopuon ofpathogen inactivadonOfplate19t components:impact on PIatelet and red b109d Cdl compoコ vent use ‐ : メ %れ Craンル Ose″ σ ち働 αη協,Doya力 ,■α“″れ“ Dafoれ ,Caci7σDabび ■4″″ 呻 翡, 力 Oydο れ為ル グ″ B οζ L れ αれ′こあ“んれぁ c a 法 ん 磁 Йα″9 昨 s s ' M α“ σ1 / a 助 ヶ ル ゅ 昭 J η, L J ″ uring the past four decadesmultiple new procedures and practices have been introduced to improve the safety and emcacy of platelet plateletpheresis, preparation of whole blood-derived buffy coat PL[s, additive solutions (ASs),process and filtration leukoreduction, initial blood draw diversion, and gamma irradiarion.'Addidonalinnovationsto detectbac. terial contamination,, change the PLI transfusion threshold,3 reduce thq incidence of alloimmmization,. and change the PLI trmsfusion dose5have been evaluated in clinical uials of varying size od scope,and mily of these innovations have been introduced into roudne clinical practice.6T In 2003 pathogeninactivationpreparationof PULcomponen$ was introduced into clinical practice in Europe.as Theseinnovativetechnologieshave been evaldatedin clinica.l trials; however, additional information regarding the impact of new technologyon blood center operarions and patient outcomes cm be obtained from the experi: ence in routine use. A recent international consensus conference on pathogen jnactivation technology recom. mended that data be collected during routine use to 'were monitor impact as these novel technologies ABBREVATIONS: BTC= BloodTransfusion Centec CUMG. Cliniqu6 Univercitaires Mont Godinne; PC(s)= plateletcomponent(s). F r 6 , t h e T r a n s F u s i o n C e n t e r a n d t h e H e m a tc oe l, oC "l S" e‐■ :qυ es unirrSItalres de Mont CollnPe U"●ersi"CathOliq●e de Louvaヽ YvoL Belびumi and cerus cOrporation,Concord, Californla ス″ `s″ ′ヴ″ぉた夕‐S●`ο :Laurehce Corash,MD,Cerus COrpOration,241l Stanweu D●ve,Concord,CA 94520,o‐ma■ icorash@cerus com RecelVed● pubHCa,on May15,200■ re■ ● dO,recdveo January 14.200,and a,cepted,lwary19,2099 do::10.1111/1.1537・ 2995200992151x TRANSFuS10N 2009:49:1412・ 1422 1412 TRANSFuS!ON Vollm● 491」uly 2009 MATERIALS AND METHODS Overallstudydeslgn The BTC Mont Godime collects md supplies all blood componentsfor a 400:bedceachinghospital of cheUniversitd Catholique de Louvain (Mont Godinne, Yvoit Belgium).The trIe pedorins approximately 20b0plateler. pheresis and 7000 whole-blood mUections per year to suppon a diversep:tient popu.lationwith major subpopulations cared for by hematology-oncologyand cardiovascular surgely specialists.The BTC issues all labile blood components for transfusion and maintains an electronic darabaseto record the transfusion or destruction of all issued blood components. Longitudinal trmsfusion recolds are maintained for all recipients of these componenls either in hospital or in outpatient Oeatment clinics. Data for this study on utilization of blood components were obtained from electonic blood bmk recordb and clinical laboratory records. The period from october l, 2000,to September30,2003,constituted the contrcl pedod when a.llPLI components wer'eprepared without pathogeninactivation treatrnent,and the period from Noyember 1, 2003, tbrough October 30, 2006, consrituted the test period'when all PI-II comporientswere prepared with parhogen inactivation. One of the authors 0CO) has been the medical director of the BTC during the entire period covered by this study and supenised the hemovigilance' progiam. Individual patient infomed consent was not required to obtaln the data couected as this study was conducted uder the existing hemovigi.lanceprogram for the BTC in compliance with Belgiari Law to monitor the impaat of nil technologies on blood transfusion practice.Ia Patient privacy was protected undtir the hemovigi.lmce progrm. Collectlon and preparatlon ot PLT components Contrcl peiod Duing this 3-year period 85% of PLX components were collected on a cell separator (Amicus, Fenwal, Inc., Round Lale, IL) and 15% on another ceu separator (Spectra, Gainbro BCT, Boulder, CO) with process leukoreduction, For components collected on the Amicus device,T-Sol PLI AS (Fenwal,lnc., La Chatre, France) was used in a rauo of approximately 35% plasma and'659o T-sol. For components collected on the Spectra device, PLls were sus. pendedin 10070 plasma.For borh platfoms, components were prepued as conventlonal PLf components in compliance with national regulatory requirements. A.ftercomponent preparation the PlI concentlations (l0e/L) and. the volumes (mL), baied on weight, of each component were measuredand the tota.lPLIdoEe per component waq calculated (10!t P[fs). PLI components were treated with gamma irndiatjon as required for patient Specific indicadons, and tested for c)'tomegalovirus (Clvfv) utibodies as required for patient specific indicatiohs. During this period, PUTcomponents were stored for up to 5 days. Test period Duting this 3.year pedod all PLI components were collected on t}le Amicus cell sepeator (Fenwaj, Inc.) with procesg leukoreduction and with the Intersol PLI AS (CerusEurope BV) in a ratio ofapproximately35% plasma and 6590Intersol. After collection, the PLI concenrmtions (1o'g/L) and volumes(mL),basedon weight, ofeach component werc measured and the tOta.lPLf dose was calculated (10'r PLTS).These components were prepared with pathogeninacdvarionunder the CE Mark regisEatlonand in accordance with national regr:Jatory requtements. Within the nret 24 hours after collection, all PLT components were treated with pathogen inactivation (150 [mol/L amotosalen HCI and 3 j/cm, UVA ligh!,920400 nm) accordingtothenanufacturer'sdirectionsfsruse (INTERCEPT, CerusEuropeBV). For quality conrrol (QC), the final volumeofueatedPLTcomponentswas measured on approxinately 30% of components and used to estimate the final PLI content of each component based on volume loss.Patlogen inactiwtion treatment was used in place of gamma irradiation and CMV serologyresdng to meet specific patient indication requirements, and it was used instead ofbacreria detection to meet national regula. tory requirements.With pathctgeninacuvation ueatment, PIX componentswere.stoledfor either 5 or 7 days in accordmce with nadonal regu.latoryrequirements. Duing both study periods, blood qenter opEmtional logisticspermitted issumce of PLTcomponents within the Vdum●491」 uly 2009 TRANSFuSiON 1413 い∞ BACKGROUND: Palhogeninactivationof platelel(PLT) components(INTERCEPTBlood System,Cerus Eurcpe)was lmplementedlnto rcutinepracticeal a blood center supporllnga leniary iars hospital.Uillizs. lion ot plalel€l components(PCs) and red bloodcell (RBC) componsntswas analyzedlor 3 y€a6 betor€ and 3 years att€r introduciionof pathogeninactivation lo assesslhe lmpactol palhogeninactivationon comDongnluse, STUDY DES,GNAND METHODS;This was a retfosp6ctiv6 analysisot prosp€clivelycollecteddata.An eleclronicdalabass used In roulin€ bloodbank hemovlgilanceto monltorproductionand use ol bloodcomponentswas analyzedto asse$ clinicaloulcomes. RESULTS:TEnsluslon recofdswere analyzedtor 688 pati€nts supporledwith conventlonalPCs and 795 patlsnts supportedwlth pathogeninactivationPCs. Additionalanalysgswors cdnduct€dlor intensively transfusedhematologypallenls.Patienldemographlcs (age €tegory sex, and diagnosticcategory)were not dltfsrent in the two obsarvatlonpedods.Fof alJpatienls, mean numbers of PC per pallenl were not ditlersntfor convBntionalPCs and pathogeninactlvationPCs (9.9 l 19.5vs. 10.1t 20.9,p = 0.88).Datafor h6malology patients(272 @nventionalPCs and 276 patho. g6n inactivalionPCs) confirmedthal days of PLT supporl were nol ditfsront(31.6 a 42.6 vs. 33.'11 47.9, p = 0.70) nor was total PLT dose ('lo') per patient ( 8 7 . 3t 1 1 5 . 4v s . 8 8 . 1I 1 1 1 . 6p, = 0 . 9 3 ) .R B Cu s e ,f o r all patientsand hsmalologypatienF, was nol dill€rent in th€ two obseNatlonpeiods, Bitherduringperlodsof PLT supportor outsids periodsof PLT tEnsfusion suppon. CONCLUSIONTPathogeninaclivatlonof PCs had no adveBe impact on compon€nlus€ durjnga 3-year obseruallonperiodol routin€practice. adopted.roIn 2003 the Blood Transfusion Center (BTC), Cliniques UniversitairesMont Godinne (CUMG), initiated unjversal routine uie of PLf components prepared with photochemica.lpathogen inactivation treatment (INTER. CEPT Platelet System,Cerus Euope BV Amersfoort, The Netherlands) for transfusion support of patients with thrombocytopenia. Three randomized conuolled clinical trials ivere cdnducted wjlh this pathogen inactivation technology in support of CE Mark registration,tr'rr but data on component-utilization were collected only for conduct of clinical trials in which the experimenta.lcomponents were produced in limited qumtities rather than in rcudne production. The BTC MontGodinne is the sole source ofPLI components and thC principal source of red blood ceU (RBC) concentrates.fora teniary care mbdical center.The blood center collects data on the use of blood components under the auspices of a lemovigilance progam. We conducted a analysis of the utilization of PLT and RBC components for 3 years before the adoption of pathogen inactivation technolog!' for PLTSand-for 3 years after the adoption of this t€chnology to evaluatethe impact of this new technologyon component utilizationunder routine clinical pmctice conditions. ROuT:NE uSE OF PATH09EN:NACTiVATED PLT COMPONENTS OSSELAER ET AL. 一 叩 匝DI輛 ￨ :1熱￨￨ 1414 TRANSFUSTONVolume49, July2oog RESULTS yielde,andprocessing PLTcollectlons, losses Dwing the coirtrol period, 5576 collectiom were performed with a mean yield of 6.28x l0!r PLIS. The 95% TABLE L Oemographlcsot all patlents recelvlng PLT comDomnts In lhe two obaeryatlon Derloda Study periOd Pa‖ents(n) Moan ago,year9 s16(%) 17・ 64(%) control Test p Vauo 795 60 8 62 9 0 01 09 10 497 45.3 688 ≧6o(・ /.) . 494 537 02' Maレ(%) 62o 623 087 Plmary diagnOsに (%)十 日omat91。 9y 305 347 0nco ogソ 65 88 ′ CV Surgery 31 7 34 7 0`he■ 222 218 012・ ・Represonls p Va ue forlhe diSllbuton i od by plmary gnosに dほ based on th● l Panent,were dasu“ ■di,O d bl∞ :dllCal service pr●mediCal care and ordOlng ord medca ‡The de● gnalbn ol other rolett lo pabnt on geぃ 。 SerVり S and sur91ca ● s● ●● lぃ 0「 vascuL子 ( 9V) γl● lan cardl● 摯]tiЪ 計器寵路器棚ξ 計 稲喘'9 Patients (n) Mom age, years ('/d < r 6 (o/.) 17-64 (%) >6s {%) Male (%) Primary diagnosis(%)1 369 Homalology on@logy CV surgery 193 1 019・ Olh€r+ ' Bepregentsp value fd the dlslributon. i Patientsivere classifigdby prima.i dlagnogisbsed on the . clini€l serylce providingmedical car€ ancl orde.ing blood compon€nt9, + Th6 dosignationol oihor rofe€ lo pationls on g€neral medical servicesand surgical s€Mces olher lhan cardiova€cular(CV) surgory | 2 .3 4 5 6 7.10 r10 FlB. 2. The dtstrtbution ofthe p€rlods ofPLT trusfuslon oupport for all patients rec€lvlng PLf compon€trts.The ftequency dlstribudon ofthe perlods ofPUT rupport for patlots during the perlod before INTERCEPT (p;e.tBs, f, D = 688) ud the perlod after IIIITERCEPT (post'IBS, r.|; n = 795) wai detor mlncd,Th€ proportlon of patients lseryEsscd on the ordlnale md th€ nmbs thiabrclcoa.Therc of perlods of PUI transfu6lon rupport on wd no itstlstlcrl budon of suppon cycls betwn dlf€me obsemtlon l,n the dirtrlpertods, Volumo 49,July 2009 TRANSFuS:ON 1415 〇い Dudng both study periods, primary care physicians ordered all blood components per standard ofcare. A proportion of patients had multiple PLT transfusions and multiple periods of PLf support during the 6"yea observation period. A peliod of PLT support was defined as the interval between the fir6t PLif transfusion and all subsequent PIjf transfusions with lessthan 5 days between PLI transfusions. If an interval of more than 5 days occurred between PLf transfusions, then a new period of PLT support was considered initiated. The total duration of PL:I suppon foreach patientwas defined as the nmberof days between the first and the last PLTtransfusion within the same period of PLf support. The days of PLI support for mu.ltiple periods were summed to obtain a total dwa. Data ftom the BTC were extractedinto a computer d'ata. broe (SAS,SAS,Inc., Cary NC). Valuesfor all continuous vadables were summuized as mean md stmdard, deviation (SD), median, and rmge. Differencesin mean values between the two observation periods were compared by two-sample t-test for continuous data and Fisher's exact test fbr categorica] data. Diferences in median values between the two obseryarion periods were compiled by the two-smpleWilcoxon test. A.llp values.reportedwere two-sided, dnd statistical sigiincmce was decltred at a p va.lueof less than 0.05. For the complete patient populdtion receiving one or more PLI components in either period, the mem number ofPLI transfusionsupportperiodsand the distribution of support perjods werc not statistically different (Fig.2, Table 3). The mean duration of PII support, the mean number of PLT trmsfusions, the total PLI dose, and the ● ２ ot PLT and RBC comDonents snd data Utilizatlon ol PLT and RBC componenls ︲ ０ ５ ” ︲ ２ 餃 ６ ４ Oata analysls and statistical methods Transfuslon coll€ction Patlent populatlohs and demographics Duing the control period, 688 patients received one or more PLT componentscomparedto 795 patientsdudng the test period (Table l). The incrcased number of patjents in the test pedod reflected increased clinica.l activity as qew cltrical programs were implemented at the CUMG. Patient demographics with respect to age distibution, sex, and priinarydiagnostic categorydid not differ significmtly in the two t{eatment periods (Table 1). Duing the tvvo study periods apprcxiinately.90% of the population receiving PLI support ajso required one or more RBC concenEates,md.the demographics for'these patients did not change significantly during the two periods (Table2). ８“け ｍｍ囲 一 加 ８ “¨“４ 1珈 ￨ 鮒 職 ■ 珊 m l cenual interual for the distribution of transfused dosesin the control period ranged from 2.1 x lot ' to 6.3 x l0r I PLTS. Duing the test period, 5997couectionswere performed with a mean yieldof 6.82x 10'r PLIS.After roudne implementation ofthe TNTERCEPT technology, 12,002products were treated with pathogen inacdvation. Approximately 50% of collections were targeted as double.dose collections and were divided into two rhempeutic PLI dDs6. The 95% central intenal for the distribution oftransfused doses ranged from 1.9 to 5.3 x l0Ir PLTSduring the test period. Eight pathogen inactivation procedures had technical failures (0.06%),of which 5 were due to operator eryorand 3 were due to dispojable failues associatedwith incorrect placement of a clamp dwing storageleading to plnhole leaks.ASpai't ofthe QC process,4066components dwing the test period were assayedfor volume loss during pathogen inactlvatlon processing. Mem volume loss without accouting for addition of motosalen (15 mL) was 8.2 : 2.2% md the distdbution of volume losses exhibited a 2stl pe&entile gf7.o% and a.75thpercentile of 9.4%.Volume loss correlatedwith PLIloss. With consideraUon of the dilution due to additiori of.motosalen (4.4%), tle-mean prgcessing loss was 12.6%. 幅一 秘叫叫″螂秘協叫 tion of support for each patient dudng each observation period. These deflnitions were based on tie assumption that ifno PLI tmnsfusionswere required after a s.day interval then trusfusionDeyi dependent thrombocytopenia was no longer present. These definitions have previously been used in randomized clinical trials to eva.luatePLI tEnsfusion therapeutic efficaryrLrs The BTC Mont Godinne entered all blood components into an elecuonic databaseat time ofcollection and labeling (Blood Bank Management System, 45 In-formation Systems, Minthorne, UK; or CTS Serueur,INLOG, Limonest, France).When components were issued for trmsfusion a standard form accompanied each component and was returned to the blood center after transfusion or with uused compon€nts. No patients were excluded from this analysis, The BTC maintained a longitudinal Flg. l. Oparadonal loglstlG fo! productlon ud r€leNe ofPLT oniponents uslng - conwDtlonal uansfusion tecord for each patient supthre methodc. BefoDcultud tating wlthout bacterlal {ltuei bqcponed with blood components includteilrl cultwe o @nwntlonrl tqtlng b'l$ bactorlsl cultw; 6d INTERCEPT patho. tng unique patient identification data, g€n lnacllwdon wlth conrentlon.l t6tlng, clinical seruicelocation for trdnsfusion, unique blood component identification same time frame after couection, testing, aDd pathogen number, date of tmnsfusion, dose of PLI component (Fig. inactivation tfe4tment t). The preparation of RBC transfused, and age of PII component transfused. The concentrates did not chilge in my substantial mamer BTC obtained patient clinical laboratory data from elecduing the 6-year study observation period, ild all RBC tronic laboratory records linked to unique patient identiconcentrates were leukoreduced by flltration during bot}! fication recordswith protection of patient confidentiality periods. RBC concentlates were treated with gmma kraunder the hemovigilance program. Usihg these electronic diation and tested for CMV antibody per specific patient data capture systems, greater than 9970of issued blood requirements using the sarne methods in both study components were traceable within the system. periods. ROur:NE uSE OF PATHOGEN:NAC■ VATEp PLT COMPONENTS OSSELAER ET AL mean dose of PLTSper day of transfuTABLE 3, PLT lransfuslon support tor all palienls betor€ and after sion supportwere not difierent between adoolion ot oathoqan lnactlvallon lr€atment ot PLT comoonenls the two ireatment periods (Table3). For Parmeler P Va|!e patients receiving both PLT md RBC Numbor of palients (n) 688 795. 0.01 components (control, 629;test, 721),the Periods of PLT supporl (n) 2.2 \3.2) 2.2.14.4\ 0.86 mean numbers of RBC concentrates Days of PLT suppod (days) 14.2 (30.5) 13.1 (32.0) 0.49 (n) (20.9) Transfusions,/patienl 10.1 9.9 0.88 (Table 09.5) per patient transfused 4) were Transfusion€i/dayof suppori (n) 1.0 (0.5) <0.01 1.1 (0.6) not different in the two obsewation Total dose/pEtienl(1011) 41.5 (82.8) 36.7 {76.5) 0.24 periods (control 16.5t 20.9 vs. test 4.2 (2.1) Dose per day oI suppod (10rr) 4.0 (2.3) 0.20 16.5+21.5,p=0.98). ' Dala presentgd as Deu (SO). Because RBC concentrates may be transfused to correct anemia due to blood loss or malrow hypoproduction arising from many different causes,we IAELE 4. RBC use bi all patlenb during the ob8erustlon periods, also examined the use of RBC concendurlng p8rlods of PLT support, and oulslde perlods ot PLT suppgrt trates during periods of PLI transfusion betore and atler adoptlon ot pathogen Inaollvation trsalmenl ot support and outside pedods of-PL[ . PLT comDonents uansfu sion support to determine if there Paramel€t were difierences duing transfusion. ABC υ se dua,g the θ ηr17o oお θ′ var"ρ θ″οd Patlonts(n)十 dependent thrombocytopenia ild out 1511(205) RBC un“s′ 150(2'p) palent(n) side.periods of trmsfusion-dependent FBC use during lhe entire obseNation peiod thrombocytopenia. No significilt difPalents(n)ll RBC unlsfpalont(n) 165(200) 16S(215) fer-enceswere obsewed between study 月80υ● ●“rl● er10dS O/PLア 9uppO″ 9 ρ periods in the use of RBC components Palonts(n)§ 545 duing suppon of thrombocltopenia RBC un19,alont(n) 104(144) 107(162) 071 and outside periods of PLI component tmrsfusion support 0able 4). RBC un19ゆ 9,4{145) a‖ ent(n) The broad patieni population sup' All valuos exprs$ed as mean (SD). : ported with PLT and RBC components with Patienls transfused PLI componenls during th6 obsoretion period, i was heterogeneous with respect to t Palients tnnsfused with RBC @mpon€ntsand PLT @mponentr during tho entir€ obsetoalion p€iod. primary diagnoses and the level of PLI S Pali€nts transfusedwilh RBC componenls duilng perjods of PLT kanslusion support. support required; To mole specifica.lly ll Palionts transfusgdwilh FiBC componsntgoutsido periods of PLT transflsion support 4enne the impact of pathogen inactivation on PLT component therapy, the subset of hematology patients.was analyzed separately included patiens who received Ptirs without RBC EsnsThis population required more intensive trasfusion fusion duringPLTsuppon and patients who rceived both support with less acute blood loss due 10 surgica.l interPLI md RBC suppon. We obserued no significant difier. vention and, thus, was a more homogeneous tropulation ences il use of RBC components by hembtology patients in which to evaluate both PC and RBC use. The majodty during the entire obseNation period during periods ofPLT (more than 60%) of hemamlogy patients had more than support and outside periods of PIJI srippon (Table6). one period of PLt transfusioil support (Fig. 3). The disuiS'irnililly, data were ana.lyzed fo! a population of butions of the periods of support wele not statistically oncology padents fotlowed dwing the 6-year obseryauon difereni between the two obsewation periods (Fig. 3). period. These patients were less intensively transfused with PLI components thm the hematology patients, but Hematology patien$ were more intensively transfused with PLf components, had more pedods of PLf did have multiple pertods of PLI supporti however, the suppon, and had more days of PLT support than the distdbution ofperiods of support was not different (Fig. 4, general patient population (Table5). Comparison of the Table 7). Significant differencesin favor of INTERCEFTPC were detected in uilsfusions per patient, tota.l PLI dose, two obseryation periods demdnstrated no significant differences in the mean number of PUI transfusion support and the doseper day of suppon.Therewereno signifimt periods, mean number of days of tEnsfusion support, differences in RBC concentrate use during the entire number ofPLI tnnsfusions, the dose ofPLTs, nor the PLT obseruationperiod for patients receiving PLI transfusions dose per day of PIJI support (Iable 5). We examined the and for patients receiving PLT and RBC components (Table8). use of RBC components for hematology pauents during thd entire tnnsfusion period as well as during md outside To examine the impact of trusfusion practice and periods of PLI support (Table6). ln this malysis we clinical responsesto PLTud RBC transfusions, the mean 脇ρ θ ″Pこ r:そο ″ :[1:濡 :β i紺 炒 1416 TBANSFUSIONVolume49. Julv2009 and media lowest daily PLf counts were determined on a per-uansfusion basis fbr the various patient populations duing both obsenation periods (Table 9). we did not analyze data for the oncology patients due to the small o/・ . “ =ち number of transfusions; however, we did analyze data こ2 0/0● ・ separately lor cardiovascularsurgery patients since tliey receivedPLI uansfusions at higherPLT count levels.There was avery broad and asymmetric dlsuibution ofthe daily lowest PLI count for all patient groups, md the median values werc considerably different fiom the mean va.lues. The proportion of PLI.transfusions with recorded PLI | 2 3 . 5 6 ruo rlo.. comts in the medical record on the day of transfusion was similar in each period for each patient group (Iable 9). Flg. 3. The di6trlbutlon olrhe perlods ofPtI trestuslon Whi.le-themean valuesfor the daily lowest PLI count were support for hematologypatients rcceh'lng PIT componento, significmtly higher (p < 0.001)in the test period for all The freguency ailstrlbudotr of the perlods ot PI-;f support fo! patient groups, the mediil values were not statistically patlents for th€ perlodbefore INTERCEPT (pre-IBS, * different (p = 0.23).Exploratory analysesusing ana.lysisof n = 2?2) ud the perlod qfier TNTERCEPT(poit-I85, ir; covuiance (ANCOVA) models were perforrhed on the n = 276) was deientrlred.The propoition of patlents ls transfused PLI dose with the nadir of PLI: count included expressed on the ordlnate ud the numberofperiods of PIT as a covariatein the models.Treaunent group (test vs. trusfuslon support on the abscts&Thec ws no statlstlcat conuol) and patient's primary diagnosis (hematology, dlfferene In ihe dlctilbutton of support cycles beMen obser. oncology, cardiovascular surgery, and other) were also Etion ireriodr. included in the models. Results from these exploratory analysesshowed that, within each treatment group, the adiusted means (after the adjustment Paranetor for the nadir of PLI count and/or theFl Numbef of patients(n) 276 272 primary diagnosis) were nearly the.O\ 4.1 (6.9) Porlods of PLI suppod (n) 3,7 (4.6) 0.40 Duratiorofsuppon(dbys) 31.5(42.6) 33.1 (47.9) 0.70 same as the unadjusted sample mems, Translusionvpalient(n) m,S Q7.1J 24.2 {30.5) 0.17 and the obseruation ofsignificant differTranstuslonvdayof supporl (n) 0.8 (0.4) 0.8 (0.3) 0.13 ences for the mbans and the nonsisnifi(101t) Tolaldose/pailerit 87,3 (115.4) 88.1 (111.6) 0.93 cant difference for the median re-main 3.2 (1.4) 3.0 (1.3) Dos6 per day of$pport (10r') 0.12 ' Data prosented m€an (SD). unchanged with and without the adjustas ment for the nadir of PLI count and/or the primary dibgnosis. To further,ercmine the impact of TABLE 6.RBC 180 by hematology pati071tS dψring tぃ 。o160rVatlon the adoption of pathogen inactivation periods,dur;lg peFiOd,Of PLT support,and outsid9 periods of PLT ueatment of PLI components on RBC use as a surogate measure forbleeding, we determined the me.ari daily lowest p Value Parmgter Test' Control' hemoglobin (Hb) 'level per patient for . . Pstienls(n)t 272 276 those pauents receiving both PLI and RBC unis palent(n) 24‐ 5(271) 264(304} o43 RBC concentmtes (Table l0). No difRBC use dulng the edire obsetuation petbd ferences in t}le mem lowest daily Hb Palent ln)‡ 257 266 RBC un“ずいal ent(n) 250(272) 274(305) 055 level were detected in any patient FEC IJsθ e rl● ● ●0′PLT sψ ″o" "●ng ρ groups before and after implementa)§ 222 Pa10ntS(い tion of pathogen inactivation for PLT 176(233) 054 FBC unIS7palent(n) 1 164(191) RβC υ sθ● ●tst“perOd●0′PLT suppO″ . c6mponents, 勝 :魔 』肝盟 mf器 1鶏:キ l電 ま 辮 脚 謬蹴 mttξ SIPP° “bd° ・and al,r♂ ・ “ On treamen :騨 毬:L:1習 躍en haCI∼ PaJonts(n)‖ RBC un‖ypa‖ont(nl 127(188) 12,7(192) l o0 ' Ail vdus express6das ngan (SD). i Patlgnls tEnsfusd wlth PLT @mponenlsdurlng lh6 obseryalion peiiod, t Patignts lranslusodwlth RBC @mponentsand PLT components dudng the entir€ ob$Nation dgriod. $ Palienls lransfusodwlth RBC componentsduring periods ol PLT hansfuslonsuppon. ll Pqtients kansfu€edwith RgC compon€ntsputside pedods of PLT transfusionsuppofi. otscusstoN This study provides an assessment of the impact of pathogan inactivation on the utilization of PLI and RBC components in both broad and Volume49,July2009 'FANSFUS,ON t4t7 OSSELAER ET AL ROυT:NE uSE OF PATHOGEN,NACT!VATED PLT COMPONENTS ２ ７ ︲ ７ ︲ ∝ ９ ” “ ° nl 器篤斧「 :il案 :ご :::(1蓼 ざ ０ ● ０ ● ０ 。 叫叫 慨 班 ｎ 1410 TRANSFuS!ON Volumo 49,July 2009 period after inplementation of pathogen inactivation. This required an additional l0 minutes of donbr couecUon Pahm€ler time, but was well rclerated without tnpact on donor recruitment or reten6812 7994 42(10) 36(09) く tion, For the broad padent population, 0001 471(714) 6351953) ゛ 001 adoption of pathogen inactivatlon for MoJah PLT cOunl(1007L). 220 039§ PLI components had no significilt Cardlo1/ascurarsmpa″ “・ PLT'angOい onS ln)・ : impac( on utilization of PLI compo534 ' 43(10) 38(08) く 0001 PLT doso/1ransfusbnf nents as measured by multiple indices PLT count(10'た 7112(514) 774(451) 009 ll including mean number of trmsfusions M o d a n P L Tu ∞ nt“ 03/L) 68p . 0005§ 10gy″llerrs わ θ mal● per patient, mean total dose of PLTSper 4″ Ptt lrans● Ыon,(￨)▼ patient, or mean PLf dose irer day of PLT O,se/trnsfu● 42(10) 。 nl 36(09) support. The only.significant difference PLT Count(100■ 4411723) 60o1973) lq Modan PLT count“ 017L) detected was an increase in the mean lnte nsively t@nslu$od hqlalology paliqls" number of PLf tran{fusionsper day of supportfrom 1.0to l. I (p < 0.0l) among 36(09) . 42(10) 440(7201 605け 7) the broad patient population, This difModan PLT ooun`lo■ 〕 fererice may have arisen due to a small Th6 tolal numbgr of PLT lranslusionsadminisleredduring each poriod wilh at l€ast decreasein the mean dumtion of PLT one PLT count on th€ d€y of transtusion, support from 14.2to 13.I days (p = 0.49) The m6an.(SO) tor he PLT dos€ (101r). after implementationof pathogeninac. The @n daily lowsl PLT counl {SD) for lranslusionswith a PLI qount availablein ihe medical rE@rdon dEy of transtusion.Dlring lhe conlrcl and tbst periods there tivationr The reason fol .the slight wsre 4690 (68,8%)and 5797 (72.5%) kansfus'one,Gsp€cliv€ly,wilh r€corded PLT decreasein the rcan duration of PLI counls. suPPon ls unclear. Becausethe decrease Bas€d on two-saml€ Wilcoxon lesl. (SO) Tho m*n dajly lqwost PLT count lor transfusionswilh a PLT count availabl€ in in duration of PLI support was not sig' the medi€l .e@rd on day of transflsion. During thp control and tost pedods thers nificet, we concluded that the increme N werc 320 (77.1%l and 370 (69.3%) lransfusions,r€spectively,wilh r@orded PLT in mean number of PLI uansfusions per O counls, Th€ nean dally lowgst PLT count lsD)llor transtuslonswith a PLT count availablein day was likely not clinlcally relevmt. lhe medical rg@rd on day of transtusion.During th€ cbntrol and test periodglhere This differencewas not detected among w.@ 4144 (73,2.h1stld 4914 (73.4%) ranstusiong resp4tiv€ly, with recorded PLT hematology or oncology patjents. @unF. Intensivolytranstusd he;alology patientgw6re detined a! lh6€ patiEnts who . BecausePLI transfusions are used recaivedlrc or mgre PLl'tEnstusiore In a trealmgntperiod, to support patients with either quantitaIt Th€ m€an daily lowosl PLT count (SD) for transfusionswith a PLT count available In the m€dical re@rdon day of transfusion.During the @nfol and test periodgther6 tive or qualitative PLT deficits with wer€ 4120 (73.1%)and 4893 (73.4'l.) kanstusions,.espdtivsly, with rg@rded PLT potential forbleeding, we examined the counrs. use of RBC concentrates as an indirect measure of hemostasls. While RB€ traltsfusions may be administered to nia. While it is possible that chmges in chemotherapy conectanemiaduetohypoproduction-aswellasbleeding, regimens over the 6-year observation period resuJtedin data on use of RBC support plovide a partial measule of less intensive manirwsuplression minimizing the impact the impact of PLT transfusion on prevention of bleeding. of a change in PLf component use, severalfactors argue For all patients supponed with PLT componen$ in either against this effect. Firet; the mem duration of PUf uansperiod, thele was no impact on the requireinent for BBC fusion support and the number of periods of trmsfusion Eilsfusion after introduction of pathogen inactivation of suppon were sinilar ln the two observation periods, ind! PIT components. This trend wre consiste4t for patients cating that chuges in prirnary disease treatment had supported with PLI and RBC components during periods minimal impact on the marrow suppression md .the of PLTsuppoil, when patients would be at greatest risk for extent of transfusion-dependent thrombocytopenia. In bleeding, and outside periods of PtI suppon when RBC addition, the similar use of RBC components dudng and use would be most reflective of transfusion to support outside periods of PLI support in both obseruation hypoproductive anemia. perlods is consistentwith a lack of change in hema@poilhe broad patient populauon included a substantial etic function secondaryto primary dise'asetherapy. proportion of cardiovascular surgery patients (approL Implementationof pathogeninactivationdid result one-third of the popuJadonin both periods)with shortin mem PUI loses of 12.69o.This was pariially compentem PLI support and obligatory intraoperauve b)ood sated for by. collection of larger PLT doses durlng the loss.To examine the impact ofpathogen lnactivation in a TABLE 9. Dally lowssl PLT count tor pallents transtused before and after adootion of Dsthooon lnactlvatlon tr€atment bf PLT comoonenlg 仰⑩塞 ⑩田ホ adoption ofthe newprocess. In additior to providing inJolmation on the impact of the inno!"tion, the study provides Pa€met€r p Value information on the utilization of PLT Numbor of parl€nt8 (n) 45 70 and RBCcomponents in a broad patient Perlods al PLT support (n) 2.0 (1.5) 1.8 (2.6) Duratlon of support (days) popr:Iation and in specific' patient 7.9 (11.2) 5.0 (11.0) (n) Transfu6ionsr'patlonl 6.8 (9,1) 3.9 (6. t) populations s'ith more intense transfuTransfusions/day of Eupport (n) 1.O (0.4) 1.0 (0.4) sion requirements. Td our knowledge, Total dose/patienr(10'11 27.5 (A7.71 14.5 (22,5) this is the first study to examine the Oc€ p€r day ot support(10r') 4,3 (1.7) 3.7 (1.4). ' impact of a newlLT preparation techDala presenlgd as m€En (SD), nology on the routire produciion and utilization of PLI components for m obsewation period as long as 6 years. TABLE 8, FBC usa by oncology pstlsnts durlng In PhaseI and 2 c.linicaltrials with autologous radiolhs two ob&ruatlon pe.lods, before and aflar labeled S-day-old PLI components transfused to healthy adopllon ot pathogsn Inactlvatlon trealment ot PLT components subjects, we detected a lSEo to 20Eoreducrion in PIT c。 嗜ro° ■ p Value “t' viability.rsSubsequently,a large Phase3 cllnica.ltrial dem摯 ramaer Fac υse d● rla9め●● りο Л ′ ″ヵ a9● a17● ●ρθ/fOd onstrated increased utiliation of PLf components trcated 45 70 P a u e n t s (:n ) 十 with pathogen inacdvation compared to conventional RBC unls/pat ent(n) 86(90) 80(77) 073 PCs.t2This observation was due in part to di.fficultieswith 88C u"`″ ″のク"θO″"●● ●9en/ationρ θr7● d Pattents(n)‡ 38 57 production of consistent PLTdosesduringthe clinical trial RBo unnS/pallent(n) 102(90) 00(7● ) 086 and the suingentrequirementto avoid of-protocol uans・ A ‖v a u e s e x p r e " o d a s m e a n ( S p ) fusions.r2Ana.lysis'of patients in both trearment groups I Palents transfu80d Wnh PLT components durng the observa´ supported with. components consistently containing “ on P● ‖ od h RBC cOmpOnents and Pけ oompo・ l Palents transtused w“ more than 3.0 x l0tr PLls, showed no difference in utiliza" nents dunng th0 0n‖ re observa6on peい od tion of PtI components.r6In light of these obseryadons, we sought to evaluate PLI component utilizadon in the context of routine practice with production of PLI componeffs over long pericids. In this study, the patient populations in the two obseruation periods were compuable with the exception of a 15% increasein the number of patients receiving PLT transfusions due to increasedclinica.ldctlvity at the study c€nte!. In both perlods, approximately 90% of patients were [ansfused with PLf and RBCcomponents providing the opponmity to eEmine the impact of the new PLT technology on use of RBG. There was considerable riuiatlon in the duration ofPLTsupport due to heterogeneityof the patient populauon, even among specific diagnostic groups, such as hemarclogy patients. This heterogeneity H,4.The`iSt■ lutiO■oFthe pe■odo ofPLT taltsfusio● reflected the diverse popr:Iation ofpatients who received suppor for oncology pad輌 ヽた。d宙 ng'LT comp● hen● .Tlle PLT suppon in clinical practice and provided a rea.listic f"quen"dお tHb6●On Orthe peHods OIPLT 3upportFor measure of the impact of a new technology. In addition, に、 “tefore sdoptloll sfIN「 ERCEPT(pFe‐ lBS,■ ■‐45) p● the. long time of observation..in which patients experi and the period aFter:N「ERCEPT(pOSt・ IBS,ハln 870)wa● enced multiple periods of PLI support duing multipJe determtned.The proportlon oFpatlen"ls expre8Sed On Ⅲ e chemothelapy rycles contributed to the heterogeneity, crdlnate and th,■●mberofperlod9 9fPLT● ans籠siO■ but provided a comprehensive assessmentof the impact ■ cissa.There was no statis● ● “pp● ●n the ab● cal difFerence lロ ofthe new technology on component use. the dls●:butlon oFsuppOrt cycles bemeen observation A substantial number of more intensively tiansfused pel:“9・ hematology patients were available in both periods to al]ow assessmentof the impact of pathogen inactivadon specialized patent popda10ns This study,s unusualii on PLT md RBC utilization among repeatedly rransfused its scOpe,h that it tovers a relatVely long penod duringpatients. During both observation periods, hematology ce, patients received the majodty of PLI components due to VVhiCh thC new techno:ogy was used in routine prac● and“ provldOs lata frOm a c6mpaat市e pe●od beb“ longer periods of transfusion-dependent thrombocl'topeTAALE 7. PLT lranstuslon suppon tor oncology patients before and aftgr adopllon of pathoEen Inactivatlon treatment of PLT comoonenls Volume 49,」uty 2009 TRANSFuStON 1419 OssELAER ET AL: ROUT:NE uSE OF PATHOcEN INACT:VATED PLT COMPONENTS TAALE 10. Dally low€st Hb level tor patlonts trsnsfused before and sfler adoptlon ol palhogen Inacllvsllon treaLmeniot PLT Paameter ス″ρarr● ●r9 Pat enls(nソ O Valu€ 626 Hb(g/dL)2 85(11) Median Hb (g/dL) 8.6 Cdrdiovascular suqery patients Pa‖ ents(n)・ Hb(9/dl)十 83(10) Median Hb(g/dL1 82 ηa'α ス″わθ′ Ogy pa"●● Paleno(nl・ 257 85(10) 82(10) 811 Hb (s/dL)t e.0(0.7) 8.9(0.7) MedianHb (g/dL) 9.0 8.9 paliqls+ lntensivelyltanslusedhwtdry Pallent(n)・ Hb(g/dL)十 Modian Hb(g“ L) 89(06) 90 89(06) ' The numbor ot pallon|€transtusod wilh both PLT and RBC corc€ntrates Bnd a Hb levEl reord€d in the medlcal Gcord on tho day ot PLT ranslusion. I The m6& (SD) daily lowst Hb levol (g/dL)per patient for gach palienl group. t tntensivelytransfusedhematologypatienls were defrned a6 thgao palionts who r6@ived two or more PLT t€nsfusions in a troalment mrlod, more stable md intensively transfused population, we sbecjfically analyzed data for hematology patients. This subpopulation comprised slightly more thm one-third of the broad patient population in both obseruation periods, md the hematologypatients had more periods of PIJI suppon md a longer cumulative duadon of PLI support (mean, 32-33 days) compared to that ofthe general popu. lation (mean, 13-14 days). The multiple periods of PLT suppon (approx. four as the average) hcluded mmy patients repeatedly transfused during each 3-year observation period. Multiple indices of PLI component utiliza. tion including mean transfusions per patient, mean transfusions per day of PLT suppon, mean total PLI dose per patient, and mean dose per day of suppon were not statistically different between the obseruation periods. Among hematology patients, we obseryed a significantly lower PLI dose per day of PLI support (3.0x lott vs. 3.2x10'r PUts per day, p=0.05) after intoduction of pathogen inactivatiori. However, tie data for this intensively transfused population supponed during mujtiple periOds of PLI tnnsfusion over a 3-year observation period did not indicate any tnpact on PLI utilization after inuoduction of pathogen inactivation for PLI componbnts (Table 5). The hematology patient subpopulation provided a patient population in which to evalu?itethe impact of a chmge in PLI component prepilation on the use of RBCs both during and outside peilods of PII support. This population was not substantially impacted by maior t42O TRANSFUSTONVolude49, July2OO9 _i surgical interuentions, thus prcviding a more reliable estlmate of the impact of a change in PLI component on both hemostmis, as measured by RBC transfusion requirements during pbriods oi PLT support, and the impact on RB€ production, as measured by RBC transfusion outside pedods of PLf support, No significmt differences in RBC uie were detected after introduction of pathogen inactivation for PLT components. We interpret these obseryations to indicate that hemostasis and RBC production were not affectgd by a change in PLI compo, nent Preparation. We a.lsoexamined the impact of pathogen inactivation on PLI use by oncolo$/ patients. However,this was a small patient population; md rhe data were limited. Consistent with the obseilations for hematology patients,we did not detect any highly signifcant impact on PC or RBC use due to the change in PLT component; however,these observationsrequjrc con-firmation in a larger population. As an added mears to examine the impact of a chmge in PLI component on transfusion practice and clinical outcome, we exmihed data on the daily lowest PLI count and dailylowest Hb level on days of PLI and RBCtrmsfusions.We hypothesizedthat the lowest PtI count and the lowest Hb within I day on days of PLI and RBC trmsfusion, respectively,would provide a compuative indicator ofthe level ofthrombocytopenia and anemia on the day of transfusion in the two observation periods. These data were analyzedon a per-trmsfusion basis as the laboratory indices were related to specific transfuiion events. We ana.lyzedthese data for all patien$ as well as for specific subsetsincluding cardiovascularsugery patients, hematoloty patients, and intensively uansfusdd hematology patients (those with two or more periods of PLT trusfusion support). Duing the 6-yeil period of this study at CUMG, the broadly accepted clinical threshold for PLI transfusion was a PLI count of l0 x loe to 20 x 10'g/Lmd for RBC transfusion a Hb level of 9 to l0 i/dL The BTC Mont Godinne does not require a specific pietransfusion PLf count or Hb level to issue a blood component. Primarycare physicims ordered blood components based on indivilu,al patient assessmentsand their independent clinica.ljudgment.' We used the Ptl count data in two ways. First, the dailylowest PtI countseryed as a comparison ofpotential changesin degreeofthrombocytopenia between the two observation periods. For all the patient grcups ilallzed, t}Ie mean lowest daily PLI count was associatedwith a large SD, and the diference in the mean md median values was a rcsult of rhe heterogeneous distdbution of PII levels ih the lilge patient population. b(ept for cardiovascu.larsurgery patients, the median values were not signncandy different between the groups md were 2l x l0s to 23 x l0e/1. reasonably close to expectedtrans, fusion threshold va.luesfor patients withlhypoproliferative thrombocytopenia. This trend wro similat fo! more inten- sively uansfused hematology and oncology patients as well. Cumulatively, these data suggest that after imple. mentation of pathogen inactivation, patients did not experiencea lower PLI count nadir during PLI support. We postulated that the mem lowesr daily Hb level conld serve as a surrogate measure for hemostasis provided that therev!'asno indication for differential suppres. sion of erytbopoiesis by the new PLI component. We ioncluded that the simiia we of RBC components outside periods ofPLT support, especiallyfor hematology patients,supported this hypothesis.The lack ofdifference in the lowest daily mean Hb levelson days ofPLI transfusion is consistent with the conclusion that the new PLI compbnents provided adequatehemostasis. Recently, two multicenter hemovigililce studies monitoring the safet)t of 12,543PLT components transfused to 2O5l patibhts have shom that PLf components prepaed with pathogen inactivation were well tolerated when used in routlne practice.tT'r8In conjuction with theseobservadons,the current srudy utilizing longitudinal data collectedaspdt ofa hemovig0anceprogrm demonstates that PLTcomponents preparedwith pathogen inac. tivation.canbe implemented into routine practice withoui substantially impactihgPLTor RBCcomprinenruti.lizarion over a substantia.lpedod oftrmsfusion support. CONFLICT OF INTEREST receivedresearchsupponfor conducrof this6rudy ).C.Osselaer andseryeson a speakprboardfor CerusCorporation.LS.Lin is a consultant to CerusCoiporation. L. LinandLCorashareemployeesof CerusCorporation. REFERENCES l. Hanis SB, Hillltr CD, Blood manufacturing: componenr prepdationt storage, and transportation, In: Hiuyer CD, Silbelstein LE, NesEPM, Anderson KC, Roback rD; editors. . Blood tanking md transtusion Badicine. znd ed. Philad;t' phia (PA): Churchill Livingstone; 2007. p. 183.204. 2. Blajchme MA, Beckers EA, Dicbneiss E, Lin L, Moore G, Muyl.le L, Bactsial detection ofplatelers: cunent problehs md possible rcsolutlons. Transfus Med Rev 2oosil9i259-72, 3. Rebula P, Fined G, Marangoni F, Awisati G, Gugliotta L, TognoDi.G, Bdbui T, Mandelli F, Sirchia G. The theshold for prophylactic platelet transtusioris ir adults with acure myelogenous leukedia N Engl l Med 199?:33?rlg?0-5. 4. TR AP StUdy Croqp. L€ukoclte redirction md ultraviolet B illa-diation of plateleb to prevetrt alloimmuniation and refractodnss to.platelet trdstusions. N Engl I Med 1997; 33?r1861.9. 5. Tinmouth AT, FEedmu I. Prophylactic plarelet transfuslons: whrqh dosels the best dose?A review ofthe literatue. Tlasfus Med Rev 2003;17:l8l-93. 6. Slicbte! Sl. Barkgpsd, rationale, and d6ign ot a clinical inaltO assess the efFects oF platelet dose on bleeding e nts,CIin Apher 2006: topOnic Pa● .risk in ttrombOり 21:7●84 7 Sl,ぬ teFSI mdence.b,sed Platelet transfuslon ln:Gewitt AM,WInter,N.ZuOkeⅢ an K,editors Amen‐ can Socle″ o f Hematolow educatiO,prOgram book. ｀ 曖 r t a n S o c i e t y o f 邸H e2 m0 a0 t7 o●ヽ S n g t O ■, D C t 範 172‐ 8: 8, Osselaer J,Doyen C,Chatdaln C,pebry c,GofFaux M′ M e s t e N , V a n H o o y d o n k M , S o n n e t A ` B oLsully,へ S, Corash● Impa■ 。f phot。 9hemic」 treatineit(lNTER」 CEP17M)On platelet use in routihe practice 17ox Sang 200o,l Supp1 3180 ‐ 9 Cazenave,P Pro"edings oFa cOnseisus conferenoc gide ‐ 。 ns about ne"te■ pa彎° gen lnactlvatlol‐ gled● ■よ｀ nologles Clin19al eゃth plぬ ogon‐ hactivated 9riCnce■ 34, 口aり 。S Tran,'SOn Med RO宙 eド 2008′み1‐ 10 Klein HC,AnderSon D,Bemardi MI,Cabl● R,Careyt H6ch JS,Robitalue N,SIttot,ML Sma1l F Pathogen inaclva● on:maklng d9d● Ons about new techno19g● s report oFa COnsenstt conference nansFtlslo,200■ 47 4フ 2338‐ 1l van Rhё nen D I,Cullよ Sson H,Cazenave;P,Panplluon琺 Llungman P,Kluter H,ヽ しrmeJ H,Kappers_Klunne M.de Creef G,Laゃ ret M,L10ure B,Da宙 sK,Marblle S,Mayau‐ don V Flament,,Co,lan M,Lin L,Metzel P,Bucllholz D, Corash l eurOSPRITE trlal■ anSmsiOn of pOoled bu町 ∞ ",t llatelet cottpOncnts prepared ttth photochenucal , Pathogen inactivatioh treatment thd eurOsPRIrE tnal l ぬ BIood 2003,101:2426‐ 33 121 MCOユ 10uぃ ,,VeSole DH.Ben,amin R】,Shchter S】 ,,ineda a:,Coutro S, へ S n y d e r ■s t a d t m a t e r E A , L o pHea2Z‐ StFauss RC,Goodnough LT,FrideyJL.Rare T,cable R, MΨ phyS′HいVa●F4th,D辞is K,Lin Jo,MetzeI P,Corash L,Kouisoユos A,Lin L,Buchholz DH,Co● lan MG Thera‐ . c emcacy anddrplatelets saFeけ treatea胡 th a phot。 peu● 6■the SPRINT inaoiva● ¨enC」process br paulogen trial.Blood 2004:104:1534‐ 41 13 1anO永oK,Ca2en∼e,P,Юuter H,Kienレ D,Michel M, 3eHs P,uourd B,Hastka),Marbhe s,MaFudOn,Lln L. 」h I S , C o n l a n M c , F l a m e n t J . T h l r a p e d t i C e f n c saFew。 aly teated ttherelS platdets pro‐ lphCtOChemた cessed口 th an op● mlzed i● egratea set Trantmslon 2005, 45:1443‐ 52 14 Belglan Law oF 8 Dece市 ber1992 61,r市 acy prOtectl● nh r e l a t b n t o t t e p r o c」d e "aitnag aOsf pm,obrlywl:●n ■ thelaw of ll December 1998 mplementhg DireCtlve 95′ 46 EC and thelaw oF26 February 2oo3 Belgium: ｀ Belg● n statё CazOttq 2003 15 Sn17der E,Ralfe T,LIn L,Cmnoc,Metzel P,Rhelnschldt M,Bar」L,Davis K:Buこ hhoレDH,Corash L,CoJan MG: Reco“″and Lrespan Oftt hdium Fadldabded platdpts tlvatibn usingamotOslen HCl n haこ "ated“ th padloま 50 0nd UVA llghL TranShsbn 2004`41732‐ 6・ 440. lb VurphyS,snyder Ei Cable R,SI,chte,sI,strauss RC, Volumo 49,July 2009 TRANSFuS10N 1421 OSSELAER ET AL n瞥 ∬ i撃 :1ま :鷲 T錦北l° 1露 橘 ぶ器:∫ ∬ 隠温li:鰤 よ i意 よ 1鑑癬'7 ::書 術 ombocytopenial an analysis ofthe SPRINT tria1 0f chernical treatnent Vox Sang 2008;94:315‐ 231 1 ,plltelets photochemiこ auy●eated“ th amotosalen HCl 18 0ssし laeF IC,Messe N,HeMgT,Bueho I,Castroし ,EsPl‐ and ultra、 lollt A nght ttansttsloi 2006;46:2433 ● osa A,AccOrlI P,JungeくJocquet M,FlamentJ,COrash L 17 osselaer,C,Cazenave,P,Lambermont M,Carraud 9, A prospect"℃ obsOwational cohort SaFetv study of5106 Hll●at M,3a"ola L,Tardlvel R,Defoin l Wauer C, platetttransfusbns ushg components prepared Ⅲ th Mendell,Rald。 ,P.Kandel C,De M9uter R,Pab● g‖P, Delenau D,AFrOyO IL,Padr6n F,Couezec H,Corrd M, ' phOtochemcal pathogen inaclvation treatme,Trensh_ son 200■ 401061‐71 ロ ヾい 1422 TRANsFuS!ON volum0 49,Julソ2009 販後調査及び観察研究の OR101NAL ARTICLE CAZENAVE ET AL. Us●ofadditiVe s01uti9nS and pathOgeh inacuvad6n treament Of platelet comlohentS il aregionalb16odcentei3impaCt O五 ent udlzati9n dⅢ p,tient outcotteS and cOmpo■ ing i a3-year penod Piarra 9″ れα“,ル ′ ルαれ‐ νιおο″,磁 αη″J ttJJaちおαιグル磁 η″ みDαれ″Jκ ′れz Й σ たグιaror∂ ぁ ‐ rra滋 Pた ″ο 滋れ ルれ妨′ 4α″″●η みLο ,お ιИんια ″ αレル ′ ca orasカ BACKGROUND:The Etabtiss6mentFrangaisdu Sang Alsace(EFS Alsaca)succogsivelylmplemgnteduniversal use of platel€taddllivesolutions(pASs) and pathogen inactivalion(Pl) lor plateletcomponents(pCs). To assessthe lmpactot thes€ changes,EFS Alsace avalu. ated PC use, red blood cell (FIBC)componentuse, and transfusion-relaled adve6e evsnls atter imptemenlation ol thEsenew technologi6s. STUOYOESIGNANO METHOOS!EFS Atsacepro- . spectivalycollectsdaia on production,distribulion,and responselo transfusionof all blood componentswilh gEater lhan 99.5% data acquisition,Adverse€venls atlibuted to plalelet (PLT)trangtusionsw6rs coilected througha mandatory activehemovlgilanceprogram.A r€trospectiverevi€Wol prospectlvslycollecteddata was conductedcoverlngthro€ p8riods:1) apheresisand .wholeblootrerlved PCs in ptasma,2)apheresisand whols blood-derlve.dPCs with PAS, and 3) pcs pre. pared with Pl and PAS, oala on componentutitizalion were analyzedfor a{l palientsrgeiving pos in each period and tor lhe subsst ot hemalology-oncotogy' palientsto evaluale PC use in an Intenselytransfused population.Valuesfor all contlnuousvariableswe16 summaizod as mean and slandarddeviation,medlan. and range. .RE6ULTSTApproxhately 2000 patientsr6ceivedpCs In each pedod. PLT and FBC use per patient was not Increas€datt6r Pl (analysisot variance,F = 1.9 and 2.9, fespectivoly)and the lncidenceof acuts transfusion r€aclims was significstly Fduced (p < 0.001). CONCLUSIONS:UniversalusEof Pl was implemenled withoutimpacllngcomponentuse, as indicatedby total dos6 ot PLTSper pati€nt,and outcomesto lranstusion were imoroved. he Etablissement Frmgais du SangAJsace(EFS Aisace)isthe soleproviderofbloodcomponents for approximately 2 million inhabitants of the AlSace region of France and issues approximately 17,000platelet components (PG) per year.Iri 2005, the EFSAlsaceimplemented routine use of platelet addi" tive solution (pAS)for production of pcs ro reduce recipi_ ent exposureto allogeneic donor plasma and to increase salvageofplaima for production oftherapeutic and Aactionated p)asma.The following year, 2006,rhe EFSAJsace implemented routine use of photochemica.l pathogen inactivation (PCT) to reduce the risk of transfusion. transmitted infeclion md adverse immune reactions associatedwith transfusion of pcs. Each of these interventions has the potential to impact the therapeutic efocacy of pCs as wi:l.l_asimpact utilization of other blood comlionents and patient outcomes in responseto transfusion t}lerapy.,.2Component ABBREVIATIONS: CSDp = concenrated Eingle-donor plareler (program); EFSAlsace = Etablissemenr Frangais du SangAlsace; PAS(S)= platelet additiye $lurion(s); PC(s) = plareler component(s); PCT = photochemical parhogen inactivation; PI = pathogen inactivatiotr; TA-GitID = transfusion,associated graft -ve6us-hst disease, FFOm the Etabnssement Fran,als lu Sang(EFS)● lSaCe, INSERM UM≒ S949,and th,Un市 ersit`de Strasbourg,stras‐ bOЩ 3 France and cerus COrp,Concom,c・ alfornia. ′いs″″ r,"′ ″`″ ぉぉ":Jean,Pierre cazen″ 4′ e,Etablisse‐ du Sang.AIS■ e,10 me sPleimann,BP 36,67065 ■ent nanca、 Franc0 市 9‐ ‐ aJ:je“ Strasbourg cede、 plCrre cazenaveeeヽ alsace fr ・ Recelved forlЧ bHcationMarch 01,201Q●reす 6n tecelved l u l y 9 , 2 0 1 9 , a n d a2c,c2e0p1t0e d J u い do1 lo llll′ ,1337:2995201002873x ▼ ・ ・ ‐ TRANSFIIS10N・ :“ ;'“ v。lume'',・・" TRANSFuS10N l utillzation ahd tfansfusion-related adverpe events wele selected as outcome variables bemuse of clinical relevanceto patient management.A decreasein therapeutic efficacydue to changesin PCtreatment could result in the need for morb transfusion support. A change in the incidence of advene events associatedwith novel pcs would be higily relwant to both patients md treating fhysicians.To assessthe impact of use of pASs and pathogen inactivation (PI)treatment, EFSAlsace conducted a retrospectivereviewofPC u6e,red blood cell (RBC)component use, and tansfusion-related adverse events dudng three diferent periods to evaluatethe effect of each change in ' platelet (PLT) prepuation. This ieview provided usefir} information regarding the progresive effects of each change for all patients supponed with pCs during each obseruation period, md for specific patient popularions, such as pediatric and hemarology-oncology patients, which might be differentially affected by changes in the manufacture of PCs ' MATERTALS AND METHODS Overall studydeslgn component utilization becadse they are intensively transfused for prophylaxis olbleeding and provide a more stringent population in which to assesscomponentutilization. Produciion of PCs The wiables for preparation of pCs during each.of the three periods ae summarized in Table t.Whole blood ms collected into CPDA-I anticoagulant from volunteer blood donors who met the EFS requirements for blood donation. Whole blood-derived bury.coat pCs were prepared as previously described.a Single.donor apheresis PCswere colleited from qualified donors using an apher. esis system (MCS+,Haemonetics, Braintree, MA). Duing the three periods, all PCs were leukoreduced by filtration . (<l x 106white blood cellsJWBCsI/pC) to producea therapeutic PC ihat was stored for up to g days with reciprocal agitation under temperature bontol (22-24.C) befoie uansfusion. Period 1 Whole blood donation had a mean volume 6f 462 a i4 mL. Six whole blood-derived bu6, coat concentrates were pooled and suspended in IO0% donor Dlasma. Single-donoraphersis PCs were suspended in lO0% donor plasma. Dudng this period, lwo larget doses for apheresis compon€nts were used, 3,5 x 10rr or 5.5 x l0rtr) PLTSper collection, Both whole blood-derived pooledO'\ bufly coat and apheresis pCs were irradiated with 2500 ccy, using a cesim source, according to establ.ished indications for prevention of transfusion-associatedgraft. versus-host disease(TA-GVHD). The study coveredthree obseryation periods, each lasting from 9 to 13 months in duation, The variable length of each period was in part determined by the time required for swirching between types of pcs and data for each . period werc utilized only once productjon consisted . enurely ofthe new type ofpC product. period 2 was arbitrarilyshoner due to tie decision to implement pl as soon as possible. Duing the l3-month period from January 2003 to February 2004 (Period l) all pcs derived either hom whole blood collections or by.apheresis collections were prepared in 100% allogeneic donor plasma. During Peiod 2 the g-month period from September 2005 to lune 2006 Whole blood donation had a mean volume of (Period 2) a.ll PCs were prepared in pAS (53%-68%)and 460 a I I mL. Sixbufry coat concentrales were pooled and residualdonor plasma (32%,47Eo). Duing the I l.month suspended in approximatCly 35% donor plasma period from September2006ro Augusr 2007 (period 3) aU and 65% PAS (T-Sol, Fenwat, Inc,, La Chatre, France). PCswereprepared br PAS(S3yo-68%) md residual Dlasma Single-donor apheresjsPCs were coLlectedfrom qualified with PCT for PL During each of these three 132%-4707o\ donors using the MCS+ platform h'ith the concentrated periods, data were coll€cted on the production, Eansfusjngle-donor PLT (CSDP) program (Haemoneti6) and sion, ad trmsfusion-related adverse events for all suspendedIn approxjmatelj' 4570donor plasma with 55%. patients supported by the EFS Alsace. Data were collected in compliance with a national hemovigilmce progrm _TABLE l,Variables fOr preparation o'PCs with protection of patient confidentiality, and individual patient inJormed WhO,bbOd(mL) 462± 1, 460± 11 461 ■ 11 consent w6 not tequired,3 Data on AnJcoag」ant cPDA・ l CPDA‐l cPDA‐ 1 PC and RBC component use were Poo1 31zo 6 6 6 PIasrna target(%) 100 135 35° analyzed for all patients receiving PAS(・ /.) 0 65 65 PCs during each obsenation period and for the sub.s€t of hematologyP,atrOrm MCS+ Mcsγ csDP Mcs+′ CSOP Tar901 dose(x10■ 3 5 or55 45 45 oncology ) patients, Hematology. PiaSha targot(%) 100 45 45 oncology patients were selected for PAS(・/.) sepilate anal)4is lvith iespect to blood 2 IRANSFUSIONVotume.'.'... ROuT:NE uSE OF PATHOsEN‐:NACT:VATED PLT COMPONENTS T-Sol. Durlng this second period, the collection tilget for apheresis products was 6et at 4.5xl0trPLTS per coUection. Both whole blood-derived pooled buSr coat and apheresis PCs were irradiated with 2500 ccy according to established indications for prevention of TA.C!'HD. hotus ofincubatibn using a compounfl adsorption device. Apheresis PCs were released on Day I and pooled whole blood-derived PCs on Day 2 (Fig. l). PI irealm€nt was used in p,lace of gamma irradiation for prevention of TA-GVHD. Residual amotosalen levels were measured in l70 of Eeated PCsfor qua.lity control. Peiod 3 Whole blood donation had a mean volume of 461 + ll InL Six buffycoat concentrbtes U'erepooled and suspended.in approdntately 35% donor plasma and 65% PAS 0ntersol, Fenwal, lnc.). Single.donor apheresis PCs were collected from qualified donors using the MCs| ptatform and CSEP software (Haemonetics) and suspended in approximately 45% donor plasma with 55% Intersol. Duringthe thirtl pedod, the collecuon talget for apheresis products Ms set at 4.5 x lort PLTSper collection. Both pooled whole blood-derived and apheresis PCs were processed (Fig. l) within 24 hours of collection using mbtosalen-HCl and ltVA light photochemica.l PI teatment 0NTEnCEPT Blood System for Platelets, Cerus Europe BV Amersfoort, the Netherlands) according to the manufacturer's directions for use.s[n both cases,residua] arnotosalen and photopioducts were removed aftbr 4 to 8 Trangfusion of PCs and hemovlgllanc€ monitoring In i]l tlree study periods the PIJ cost and total PLT content were determined for each apheresis PC. In the fusr two periods, the PLI count and'PLT contenr of pooled leukoEduced whole bloodderived bu8' coat components were determined in a subset (3% for Period I md l79o for Period 2) of components for process conuol. In Period 3 PLI count and total PLI content was determined for each pooled leukoreduced whole bloodderived buqt coat component. PLI counts wer€ mea. sured by electricdl impedance with calibradon using an optical PLt counter (SysmexXE 2100D, Roche Diagnostjcs, Mey,lan, France). Total PLI content of ransfused components was determined based on PUf concentration md component volume expressed as toia.l PLTsx l0rt. IDayl 8 1012141618202200 IPFy2 2 4 6 8 1012 The EFSAlsaceblood center maintains a databasd to compare between.PeriodI md 2, Period 1 and 3, and monitor the production, issuance,transfusion, and utiliPeriod 2 and 3. All p values reponed were wo-sided, and zation of all blood components. The blood center data. significance was declared at d p value of less than 0.05 (p < 0.05).All statistical calculations were done witl combase contains informa0on on patient demographics and clinical seryice location of uansfusion. In each period, puter software (Excel, 2007 SP2 MSO, Microsoft Corp., pdmary care physicians ordered PCs for tmnsfusion Redmond,WA). according to French nationa.lguideline! published by the French Agency of Medica.l Safety of Health Products in 2003 and basedon a recommendeddose of0.5 x 10rrto BESULTS 0.7 x l0rr PLTSper ?kg in aduttsand 0.5 x l0rrPLTsper 5 Demographics of pallentstranstuaed wlthPCs or 7 kg in pediatric patjents for suppon of thrombocytopenia. The respolNe to transfusion of blood compo. ln each of the three periods, 167& to 2069 @nsecutive nents was monitored through the national active patients received one or more PCs (Table 3). Within each hemovigilance program under the direction of French period, the lilgest proportion of PLT uansfusions were Agency of Medical Safety of Health Products.3Under this adninistered on hematology-oncology cue serices progrm, all blood tnnsfusions are monitored and poten. (Table3). Patients ranged in age from less than ! to 106 tial uilsfusion adverseincidents ae evaluated for severyeils ofage (Table3). ity and relationship to the fiansfused component in a .tnnsfusion inciderit TABLE 2 productioh and uti‖ zat:on of PCs repoft. Declaration is mandatory 'olod l' Pe‖ o02+ Period 31 for each transfusion, whether or not 13.241 a tlmsfusion. incident repon has PLT cono耐σ“anすosed"mpohen、§ Mean dos● ′ unl(x10") occured. The severity of incidents is Median(文 lo") 6.4 47 classifiedbasedonWHO criteria: crade Range(X101り 05‐7,3 l-absence of immediate or long.term PC us″paJeni(n】 vital: threat, Grade z-potenual longPalonts 2.050 1.678 Moan 62b 55` term morbidity, Grade 3-immediate Mod an 210 20 vital threat, and Grade 4-death of $e 104 1・ 114 1‐ 289 1‐ paden(. The relation of the transfusion TolaI PLT losOわ dにⅢ IX107り ¶ Moan to the adverseeffect is eva.luatedusing a 26、 9 MOd an 109 94 five-poht scale basis: o<xcludes my Ran9o 05・1,S02 causalrelationship, I-is doubtful, z*is 'PCs were prepaァ edin plasma D● "ng Polod,,PLT 9ontOnt of who o blood‐delved possible, 3-is likely, md 4-is unqussrnpOnents PC Was doleminedin 3%Of∞ tionable. The uansfusion incident 10d2,PLT content Of who O b10od † PCS WOre lrepared n,asma with PAS Duang P。 ‐dolved PC was determinod in 17%of∞ mponenls rcports are submitted to regional hemorigilance network coordinators and entered into an electronic database. PIず 2'b円=Pe, "assu市 Pr m9 Sam響 ツ Ъ 舅i留 ￨}管 評鞘鵬3轟l珊棚 ゎ he晰 o 6二 o“ 口 “ ぶ:3提 写'1背 :L∵譜 Statistical analysls . Flg. l. Pc pro@slngwo*flowThe dne ln hours stddngwlft the day of collectlon (Day 0) ls tndlcated.Apher6ls comDoneDts are ihakere (22-24'C) followd by PI treatmen! ild lncubatlon ln a compound abrorptlon contalner from a mlnfunm of 6 howe to a maxlmum of 16 hou! before relese for trusfurlon.Whole blood ollec. rtoEd ouimlght d€vte{CAD) tloN @ ttocd on tempqstuE-@nrolled dfter couecllon, On Day I buffycoat concentrateE.re loolated, pooled, ud treeted wlfh pt fott@d by rnd releue on the beglnnlng of Day 2. rSerclogy/NAT I am.-3 p.m, dally. PI and CAD - psthogen Inactlwtlon the INTEnCBPT Blood Syrtemi NAf = truclelc acld tsting, owmlght CAD lnflbatlon uslry ●TRAIISFuS:ON 3 Vo umO",・ ・・ Descriptive anallses wele cdnducted for the demographic and clinical vili. ables.Valuesfor all continuous variables were summuized as mean and standud deviation (SD),medim, and range. A one-way anaJysisof riance (ANOVA; shgle factor) was used to test the equality of PLT content per product, of the number of PCs transfused per patient, -dose and of total of PLfs received by the patient between the three periods sudied (Table2).When the diSerenceof ANOVA during the three periods was significant, a t test was used a priod !o 4 TBANSFUSIONVolume". " " 19 9quJ va"a,60'・ 精 纏算 1群 警,Ii]儀 響照 鞘F尋 馬:盤 警珊: ¶ ANoVA The dr10rence t nol sb雨 Fcan fo「any∞ mpan10ns:F・ 19, TABLE3. Demographlcaol pallsnis lranstusad with PCs Demographic PEriod'!' Psriod 2t. Numb€r ot pati€nts ?050 1678 M€diar age (yeaF) 64 63 Age rang€ (years) 3-97 <,|.99 [4ale (%) 59 60 Ptoporlions (%) of patignl6lrtrsfused b!, cliniRl seryice Hsmatology.oncology 56.1 50.5 Gen€/el r€dical 36.6 43.6 Cardiryascularsurg€ry 7.3 5.9 ' PCs w6re p€par€d in plasma. t PCs w€re preparedin plasma and PAS. + PCs wers prgparedin plasmaand PAS wilh Pi irealment Period 3+ 206S E3 <1.106 62 58.1 96.9 5.7 ０い IDay,、 ■ TIME 8 1012141618 2022 00 2 4 6 CAZENAVE ET Aし , ROUT,NE USE OF PATHOGEN・:NACT!VATED PLT COMPONENTS Characterlsllcs of PCs Acute transtuslon reactiong During the three periods the PLT content per component changed as the methods of production changed (Table 2), With the introduction of PASS, production methods were adjusted to equalize the PLI content of apheresis and whole blood-derived PCs that were ordered interchangeablyby primary 6re physicians.All PCstransfused demonstrated retention of swirling whbn issued by the blood center. PLI content per PC unit was significantly less in Period 2 compared to Period I (p < 0.05) and in Period 3 compared to Period 2 (p < 0,05) tTable 2). Dudng Period 3, all the 13,241components were tested for PLT content; the mean I SD PLI content was 4.2 x lotr t 0.4 x l0rr and the mean I SD loss due to PI was 24 ! 4 mL containing 0.3x l0'r 3 0.07x l0r! PLIS. For PCs ueated with PI, residual amotosalen levels were measuredin l% of products (n = 201).The mean residual motosalen concenuation for whole blood md apheresis components was 0.24 10.09 pmol/L (median, 0.22[mollLi mdimum, 1.25pmol/L). Uilllzalion ot PCg Utllizatlon of RBC components Utilization of RBCs was determined for patients who received one or more PCs during each :observation period (Table4). ln each observation period, approximately 85% of patients transfused with PCs rmeived at least one RBC unit No significant difference in utilization of RBCswas detected between the three obsemtion periods. TABLE 4 uti‖ zation of RBC compOnent8 Pelod l' Number ol pali€nls tGnslu$d with PCs Number (o/4of patienls transtused wilh PCs and RBCS Number of RBC unitss Mean numbor RBC unils/paljent ' PCs werg prspar€d in plasma. PeaOd 2+ 2,050 1,715 (83.7) 1,678 1,355 (80.8) 24.693 14.4 1?132 13,1 Polod 3‡ 2,069 1,749 (84.S) . 23.824 13.6 t PCs were preparod {n plasma and PAS. + PCs w€ro prErErod ln plasma and PAS with Pl treatment. $ ANOVA.Tho dlttersn€ b€twem the lhr6 perlods is not slgnlfi€nl: F = 2.9. casesof transfusion'related sepsis were reponed in my period. The incidence of transfusion-related adverse elents per 1000PCs transfused was significandy reduced with the implementation of PAS (p = 0.005) and further rcduced with the implementation of PI (p = 0.021).Analysis of the lncidence.of ransfusion-related adverseevents per patient demonstrated significant reduction after implementation of PAS(p = 0.009) and further reduction ivith the implementation of PI (p = 0.0779). Ulillzation ot PCa by intensively transfused patlsntg To further characterizethe impact of changesin PC pro' duction, the utilization of PCs and RBCSby intensively transfused patients with hematology-oncology disorders was examined. Eraluation was resuicted to Periods I and 3 since use of PASwithout PI was only m intermediate phase in the evolution of the PLf production process at EFSAlsace.During both Period I md Period 3 all PCs were leukoreduced(<l x 106WBCs/PC),and rhe proportion of whole bloodderived bui[' coat and apheresis PCs remained constant {62;38), Espectively. Mean PLI content per PC was lower during Period 3 (4.2 x l0rr) comparedto Peilod I (5.2x 10tr)due to a decisionto harmonize the PLI contentof both t'?es of products, Approximately similar numbers of hematologyoncology patienti were tmnsfused dwing Periods I and 3 (Table6). Althbugh.the number of PCs tanstused per patient was increasedduring Period 3 compared ro Period l, the total dose,of PLTSper patient wN nor increased (Table7). The lncrease i.n the number of PCs was due td decreasedPUf content per unit in Period 3 compared to Period l. DrscusstoN TABLE 5, Adverse rcactlons alter transfuslon ot PCs Pelo0 1: Numbgr ot patienls lranslusgd Number ot componenls lresfusod Number of patients with adve.go roactions Numbor of advocs 9v€niss Numbor ol ngo alloantibodiesd€tectsd Numbor ot RBC Elloanlibodi€VloooPCs Number of translusDn reactions Number of tolal r€actions/looo PCs Number of Po{elatBd reactions/'toooPcsll Patientswith PC reacllore (%)'ll 'PCs worO pppared n plasma 2,050 10,629 59 67 11 1.03 56 6.3 5.3i" 2.9.c Polod 21 1,678 33 25 45 27・1 Poい od 3↓ 2:o69 36 18 28 14b● t PCS Wore prepandin p asma and PAS 幸 PCS WOro propュrod n p,asma and PAS inh PItreatment dotecled lo RBC antigens S TOta transFuslon reacl ons oanubodies nc uding a‖ RBC a‖ ‖T7ansfuslon reacuons exdudin9 symptOma,c oanlbod● ●not assodatodh w“ =o o5,drerOnce r oo● pく lP,_P2,p=ooOoa reaoOns Ch.squaro b“ wnh α bP2-P3,,=00214::Pl― P3,p_ア xl●t ng RBC squaro alloan“ Ch卜 teSt With ¶SymptOmalc reacJons to PCs,oxclud bodiosi α=005,d“erenCe r pく 00''Pl_P2,p_o.oo9■ IP2-P3,p=O o77a° Pl―P3, ・‐ TRANSFuS:ON 5 Volumo・・ ,・ In 2005, the EFSAlsace regiona.lblood center initiated chilges ii1 the routine p rep arati on of PCswitJ| the intro ducti on of PAS, which ms followed by implementation of PI treatment in 2006. Each of these changes had the potential to impact the PLI contett ofcomponents, the utilization of components, and patient outcoms. To assess these potential impacts, EFS A.lsace conducted a retrosptrtive analysisof three diferent periods, each of approximately I yeu duration. The comparison ofeach of these innovations with conventional PCsin 100%plasma provided a memsto assess the .impact in a controlled mamer sincethesameblood center and processingstafiprepiled PCsin each bf 6 TFANSFUSION the observationpetiods. Although primary care physicians were aware of the changes in methods of PLT production, theycontinued to prescribe PCsbased on simiiar stmdard ofcare guidelines in each ofthe observation periods. This provided approximately similar clinical conditions to monitor patient responsesin each of the periods. This analysiswas based on a comprehensive longitu. dinal databasethat tracked greater than 99% of PCs with respect to patient demographics md utilization by patients. In addition, thd response to trmsfusion with respect to adverseoutcomes ws evaluatedusingm active hemovigilance program3 for which data for $eater the 997o bf transfusions were reported in the EFS Alsace region. This study offered a sique opponunity to examine th-eimpact of these changes in PLI production when implemenredin routine use for support of a broad spectrum of patients. In addition, trus study included a substantial population of intensively trmsfused patientswto may have been more hematology-oncology sensitive to chmges in the methods of PC production. TABL● 6.Age demographics of hemat,logy‐ 。n● lents transtu:ed 111'飛 -. DomogBphlcs Numb€r oi palionls Numb€r (%) ol infants-toddlersl Number (%) ol childrens Number('/4 ol adultsll ' PCs were pr€pared in plasma. Period 1' 671 10 (.|.5) 49 (7.3) 612 (91.2) Porlod 3t 699 5 (0.7) ' 49 (7.0) 645 (92.3) t PCs \i,ere p@par€din plasma and PAS with Pl heatmonl. t lnlanls and toddlerswgr6 t honth to l€$ than 3 years bf aga. S Childrsnw€re 3 to 17 years of agg. ll Adults w€r€ greate. than 17 ys.s ot age. IBLEス U‖ p° lens'y 」 織 L:1琳謡 『謡ぶ肥 Numbor ot pationts Numb6r of PCs lranstus€d Mee : sD* Medianll Rsgoll . Total PLT dos6 M6an : SD+ M6dian Rangell Number ol RBC unils transfused M6ang M€dianll RangeJl ' PCs wsre pr€parod in plasma. 40 1‐ 264 1 ‐1 0 3 453=628 216 08・536 152■ 165 461 =861 184 1.5‐ 1189 _ 136■ 0‐ 93 t PCs were prepared in plasma with PAS and Pl t€atrnent. + Mean number at PCs lransfused p€r palignt. t Men tolai doso ot PLT3(1011)por patienr. S Mean number of RBC unlts per patieni. ll Dala expre$€d p€r patlenl. 184 0‐ 272 卜い The utiliation of PCs was determined per patient based on tlie number of compone[ts transfused and the tota] number of PLIs trmsfused per patlent. The latter was of specific importance as the PLI content per component changed according to changes in the methods ofproduction during the three periods (Table 2J. For each period, the relative proportion of whole bloodderived and apheresis PCs remained constant, approximately 6570:35%, rcspectively.The mean number of PCs gansfused per patient increased in Peliods 2 and 3 compared to Period I (Table2); hmever, the number of transfusion episod6s and the total dose of PLTStnnsfusd perpatientwere not differentbetlveenthetwopedods flable 2). AdveEe events after tlansfusion ofPCs were evaluatedfor relationship to transfusion and all events classifled.as doubdul, possible, Ukely,or unquestionablewere defined as acute ttansfusion reactions..Theseeventsalso included t}te obseruation of newly detected alloantibodies to RBC antigens with or without evidence of hemolytic tansfusion reactions (Table5). Cumulatively, for all three periods, 145 adverse events were reported, of which 46 were newly detected RBC alloantibodies without hemoly. sis secondaryto concomitant transfusion of RBCsin 85% of the patients receiving PCs (Table5). In Period 1, one death due to volme overload was reported.All otherreac. tions were Grades I (619o)and 2 (3370)jn severity.During Period3 among the 18 reportedreactionsnot due to RBC alloantibodies, eight were characterized by febrile reactions, three were characterized as allergic reactions, and one episode of transfusion-ielated acute lung injury (TnALI) associatedwith high-titer HLA antibodies from a multiparous donor was rcported during Period 3 in association with transfusion of Pl-treated apheresis PCs without exposure to my other blood components. Six transfusion reactions were not chancterized further. No CAZENAVE ET AL. ROUT:NE USE OF PATHOGEN‐ treated with PI in this study is consistent with that reported for severa.l other lilge postmarketing hemovigilance studies.ro12It is also similu to the Belgian experience of unlversal routine use of Intercept-inactivated PCs for 3 years,that enables leuning ofhow well the products function in broad populadons.t3 In addilion, the PI process was used in place of gamma Lradiation for prevention of TA-GVHD and in place of cytomegalovirus serologyresulting in the use ofa single PLTinventory with elimination of these additional tests and Drocedues. 7.. Rebula P, Finazzi G, Marangoni F, Awisati G, Gugliotta L, ACKNOWLEDGMENTS 9. Mccullough L Vsole DH, Beniamin RL Slichter SL Pineda A, Snyder E, Stadunauer EA, Lopez-Ple f, Coutre S, myelogenos leulemia N Engl t Med 1997;337:1870-5. 8. Eri Rhenen D; GullikEson H, Ceenave lP, Pamphilon D, -Ljungman P, Klutet H, Vermeii H, Kippers-loume M, de Greef G, Laforet M, LioureB, Davis K, Marblie S, Mayau- we thanktheclinicius df theA.lsace regionandin particularhol Radul Herbrecht and D! Bruno Lioue (Onco-Hematology Dep[tmetrt, CHU de Hautepiene,Strasboug,Fluce) for tbet constant helpandsuppon, Ttlerapeutic €6cacy ed saJ€tyof platelets treated with a Rduion. prccess for pathogen inactivation: the Osselaer JC, C@nave JP, lambermont M, Ganaud O, Hidajat M, Bdbolla L, Tardivel R, Defoin L, waller C, Mendel I, Raidot tP, lGndel G, De Meuter R, Fabrigli P, de la Rubia L Ariaga F, Lindes D, lanea L Cdpio N, Marty ML, Sau MA. Role ofmethylene blue-teated or ftesh-froren plmma in the response to plasma exchilge in patients with thrombodc thrombocytopenic purpura. Br t Haematol 2001;1,14:721-3. 3. Aldreu G, Morel P, Forestier F, Rebibo D, Janvier G, Herve 1994-1998. ft ilsfuslo\ 4. CeenavelP, and idcldent rcports from 20O2t4211356-64. Nei'l B, lviesel ML, kforet M, Isola H. In vitlo waluation ofpooled bufy coat platelets tr6ted with photochemical pathogen inactivatio! using motosaleo. Vox Smg 2004;86:201-2. 5. Ianerzko K, C@nave lP, lcuter H, KienE D, Michel M, Beris P, Uoue B, Hastka J, Marblie S, Mayaudon V, Lin L, , Lin LS, Conlu MC, Flment I. Tberapeutic efficacy md safety of photochemically treated aphersis platelets processed with e optimized int€grated set. Tlusfusion 2005; 45:1443-52. 6. TRAP Study Croup. Irukocyte reduction ild ullraviolet B Lradiation ofplatelets to prevent alloimmunization and rehactoriness to platelet trestusions. N Engl I Med 1997; 337:1861-9. Volume", " * Rasongles P, AngellnlTibert MF, Simon P, CMie C, Isola H, Klentz D, Slaedts M, tacquet M, SuDdin D, Lin L, Corash pared with photochemical pathogen inactlvation ueat' purpua. Vox Silg 2004;86: tru$fuslon using components prepqred L, C@enave JP. Transfuoion of platelet coDponents pre. 246-51. analy8is of immediate of 5,106 platelet trusfuslons Muphy S, Howatd F, Davis K, Lin IS, Metal P; Corsh L, Koutsoukos A Ud L, Buchholz DH, Conlm MG. Cid L Muncunill L Sasre IL, sanz C, PeEiE.\ Methylene blue-pho,toinactivated plasma vs. fresh-frozen plasma as replacemetrt fluid for plasma excbege.in P. Hemovigilance nehvork in FEnce: orgiliation Espinosa A, Accorsl P, Iunge K, Iacquet M, Flamenl L CoEsb I", A prospecrive observational cohon safety study StrausoRG, Goodnough LT, FlideyJL, Raile T, Cable R, CuposA; 2. Osselaer lC, Messe N, Hervig T, Bueno L Cstro E, Transfusion 2008;48:l06l-7 l. REFERENCES thrombotic thrombocftopenic chemical treatment, Vox Sang 2008;94:315-23. tl treatment: the eUoSPRITE tria.l. Blood 2003;I0l:2426-33. A, Del Rio L Bamirez c, Albo C, Pefls F, I . Alvaw-ilndir chdracrerizing tbe salety profile of 7{37 photo- platelet transfusions prcpared with amotsalen with photochemical pathogen inactivation treatment. SPRINT trial. Blood 2004i104:1534-41. I0. loce'progrmme don V, Flament l, Conlm M, Lin L, Metzel P, Buchholz D, Corash L ltesfusion of pooled buffy coat platelet components preparcd u,ith photocbemical pathogen inactivation photochemi€I CONFLICTOF INTEREST IPC is a memberof the Europem ScientificAdvisoryBodd of lC is m empioyeeof CelusCorporation.Hl, CerusCorporation. C1{,IM, DK,ML, IPR,GK,md MLWhaveno couflictsof interest. Dehenau D, Arrcyo JL, Padron F, Gouerec H, conal M, Iacquet M, sudin D, Lin L corash L. An active haemovigi' Tognoni G, Barbui T, Mandelli F, Sirchia G. The threshold for prophlAactic platelet transfusions in adults with acut€ ment duing a Chikuguyq virus epidemic in lle de La Tlanstusion 2009;49:1083-gl. Osselaer IC, Doyen C, Defoin L, Debry C, Goffau M, Messe N, Van Hooydonk M, Bosly A, Lln IS, Lln L,.Corash L; Universal adoption of pathogen inactiEtlon of platelet components: impaci on.platelet and red blood cell cbmpo" nent use; Ttansfusion 21}gi49il4l2.22, et ∞０ Patient demographics, in terms of age, sex, and primary care service for PC transfusion, rere comparable between the thlee periods. Each of the obseryation periods included between 1678 and 2069 patients with trmsfusion of between9l5l and 13,24i PCs and 17,732to 24,693 RBC units. Thus, this observationa.l study encompassqsa large experience,indeed much larger thm that of most clinlcal trials in transfusion medicine that have been used to support implementation of maior chmges in trmsfusion practice, such as leukoreduction md adjustment of the uansfusion threshold.5'7When adjustments were made for differences in PLT content of individual cornponents, there were no signincant differences in the total PLI dose required per patient, either for all patients or for intensively tmnsfused hematologyoncology patients. Changes in the methods of PC production did not impact utilization of RBCs, indicative of presewation of effective hemostasis during periods of PUI trmsfusion support. This obsewation is.of panicular interest with respect to cardiovasculal surgery patients and general medicd.l patients who have not been studied in the randomized clinicil triajs of PCs ceated with PI.t&'gwhile the utilization ofPCs and RBCSdid not change in responseto modificadons in PLI-processing,the incidencq of adverse events imputed to txansfusionsofPCs decreasedonboth a per-transfusion and a pe!-patient basis. This observation is consistent with the signincant reduction in acute transfusion reactions noted in a prior large nndomized clinica.l tial.e only a single case qf TRALI was reported during each of these observation periods; this case was attributable to high-titer HtA antibodies in a multipaous apheresisPLTdonor. No ctres oftransfusion-related sepsiswere leported in any period. Tho conclusions regarding efficacy and safety that may be drawn ftom this study are potentially limited due .to the lack of a blinded, randomized uia.l design. However, the study has the advmtage of comparative obseryation fieriods in a single region in which the staff preparing the PCs and the primary care physicians prescribing PCsand monitoring patieni outcomes remained relatively stable. Molewer, the study wds conducted in obseryation periods when each of the Pc methods reflected routine production practices. Thus, the study involved assessment ofthe changesin PC production under realistic condlttohs. In additiori, monltoring of patient clinical outiomes utilized objective measures, such as utilization of PCs md RBCS,and an active hemovigilance program with oversight by clinlcal monitors who were not associated with the blood center producing the blood components. On the basis of these factors, we believe that the data reported from this study indicate that PASSild PI treatm€nt can be implemented into routine pracdce without lnpacting either PC or RBC utjlization md with a reduction in acute fansfusion reactions. The experience with respect to the safety profile md tolerability of PCs CAZENAVE ET AL. :NACTiVATED PLT COMPONENTS TRANSFUSION7 8 TRANSFuS,ON VolumO・ ・ ・ ."・ 販後調査及 び観察研究の TRANSFUS10N PRAOTICE Therapeutic efficacy of platelet transfusion in patients with acute leukemia: an evaluation of methods Torunn O.Apeketh,AysteinBruserud,ToreWentzel-Larsen, and TorHeruig EACKGFOUND:Clini€l eflect of platelet(PLT)lranslusion is monilored.bymeasuresof PLT viability(PLT recoveryand survival)and functionalily.lh lhls sludy we Evaluateand comparglransfusion€lfecl msasuresin palientswith chemolhenpylnduced lhrombocylopenia du6 to treatmsnlof acule leukemla. STUDYDESIGNAND METHODS:Forty translusions (28 conventionalgammir-lrEdiatedand 12 pathogen. Inactivat€dpholochemi€l-trealedPLT concenlrates [PCsl] were investigated.PC qualitywas analyzed lmmedlalslybefore transfuslon.Sampleswere collected lrom thrombocytop€nlcpatlentsat 1 and 24 houc lor PLT lncrsmenlsand thromboelaslography (TEG) wlth assssmenls ol bleedingscore and intertransfusion inlerual(lTl). Data war€ analyzedby Spearman'scorelation.Patientard PC variablgsinfluencingthe elfect ol lranslusionwer6 analyzedby us€ of a mlxed-etfects model. RESULTS:PLT dose, slorag€ tlm€, and pathogeninac. tivationcorelatad wlth PLT rs@very bul not with PLT survival(includlnglTl), TEG, or clinlcalbleeding.Fever ws negatlvolycorrelaledwith PUTsurvivalbut did not atlecl PLTrecov€ry.Atler 1 and 24 houts, slrong cor€latlonswers obseiled wlthin measurgsol PLTviability and betwBenPLT Incfomenland the TEG valuB maximalamplitude(MA). Negativecorrelatlonwas obseryedbetwoenlate MA Incrsmentand clinicalbleed. ing slalus atlsrlranstusion 0 = -0.494, p = 0,008).PLT count Incrementsdid not corelate to clinicalbleedino $alus. CONCLUSIONS:PLT dose and qualityof PCs are lmpodanllor optimalimmsdlatetransfusionresponse, whereasdurationof tEnsfusion etfgot is influenoed malnlyby patlentvaiiables. The TEG value MA corr6. lateswith PLT count incrementsand bleeding,thus retlsting both.PLT viabilityand functionality. llogeneic platelet (PLI) umsfusions ue used to prevent (prophylactic umsfusions) and contfol (therapeutic transfusions) bleeding in patients receiving intensive chemotheiapy,r'sBut even though the risks of severetransfusion reactionsmd tIusmision of pathogens are minimlzed due to technologic progress and Fathogen reduction methods, PLtr trusfusions are not freeofcoinplications.6{ Itis thtirefore important to continue the seilch for an opti.rnal trmsfusion policy in patients receiving PLI transfusions. Larle randomized clinical uials ffi nm performed aiming , to define the optimal use of PLI transfusions;both by evatuation oftrilsfusion strategjesand by investigationsofthe influence of variables like PLI dose and transfusion triggers on the results oftreatment.3! The tests used.to assessthe clinica.l efficacy of PLf uansfusion reflect different approaches to minimize bleeding in patients. They inJluence routine trilsfusion practice as well as t}le results of clinical PLI transfusion studies.The clinical effect of PLf transfusion is monitored by measures of PLI viability and fuirctionality. In studies of thrombocytopenic patients, PL;I viability is usually PC(s) = platelet concentrate(s); PgI = photochemical treated; TEC = rluomboelasrography. From the Blood Ballk`the S“ tion for Hematolo絣Department of Medidne,and the Centre for Clinical Research,Haukeland un、crsity Hospital,Bergeni and the cades lns,tute and the lnstitute of Mediche,uni"rsity Of Bergen`Bergen,Noway ′'η“あ′″:Torunn Oveland Apeヽeth,MDi 4′′潜 Sた′rl● Blood B,nk,Haukeland vnIVersi″ HOSpital,N‐ 5071 Bcrgen, Nort7av e‐ man:tOrunn 9veland apelseふ@helse‐ bergen no ThIS■ Чdy VlaS fttded by a grant mm“ 艶 、e ttt,"he dol 10 1111′ j153●2995290902540x IRANSFuS10N 2010150:766‐ 775 50`Ap‖12010 investigatedby Lnmediate PLI gount increments, reflect. ing the PI.T lecovery together with late PLT count increment ild intertransfusion interval (lTI) which reflectsthe PLI survival.j5,er2PLT functionality mdy be monltored by point.of-care tests of hemobleeding assessmentsrer3.and stasis and PLT function like the thromboelastography {TEG) analysis.'tWhile PLI count incremdnts are fundamental in the prophylactic PLf trmsfusion stmtegy, the therapeutic trmsfusion strategy is based on bleeding assessments: In our study .we aim to evaluate and compare methods for measuement of clinical efrcacvin acute leukemia patients receMng regulu PLf uansfusions due ro severechemotherapy-lnduced thrombocytopenia. MATERIALS AND METHODS Study deslgn This prospectiveobservational studywas approved by the local researchethics cgmmittee (RegionUI, University of Bergen, Bergen, Nomay), and patients were rccruited from the.Section for.HematoJogy, Department of Medicine, at Hau-kelmd Univelsity Hospital from December 2006until April2007. During the studyperiod, all patients diagnosedwith acute leulemia expected to be in need of PLI Umsfusions. due to severe chemotherapy-induced c!'topenia were invited to partiCipate in the study. With one exception, all patients accepted. After informed wdtten consent,wasobtained, 10 patients with acute leu' kemia were included.in the study, giving a total of 188 patient-dayswith chemotherapy-induced cltopenia. Of a tota.l of 109 PII Uansfusioris; 40 PLT transfusions were selectedto be chaacterized in detail based on the following criteria: daltime tnnsfusions md data collection performed according to procedures. The study unlt was defined as the PLTtransfusion. ABBREVIATIONS: A?l = absolute plarelet inqemeDt; ITI = inlsnlar.fuaira interval; MA = mdimal amDlitude; govemmental admlnisiadoi oF● e health senices h the western pan of Non“ y Rcce市ed for publca● On June 22(290a re● ●on recelVed October 12,2009,and lccepted October 13,2009 766 TRANSFuS10N Volum● MONrrORING PLATELET TRANSFuS:ON EFHCACY Pleparation of PLT concentrates lor transtuslon All PLT concentrates(PCs)firlfilled the European requirements.rsSingle-donor PCs (n=17) were collected by single-needleapheresisprocedure employingthe elutriation principle to provide leukoreduced PUls. (Fenwa.l Amicus cell sepsator, Baxter Healthcare Corp., Deerfield, IL). Prestarageleulofiltered bufly coat PCs (n = 23) were produced by usb ofautomated procedures (OrbiSac,CaidianBcT, Inc., Lakewood, lO). Tlvelve of the 40 single. donor and bufly-coat PCs were pathogen inactivated by photochemical treatment using amotosalenand.UVAlight (Intercept Blood System for Platelets, Cerus Corp., Concord, CA). Photochemical.treated (PCT) PCs were suspendedin PASIII (lntersol, Fenwal, Inc., Lake Zurich, lL) and conventiona.lPCs in PAS U (T-sol, Fenwa.l,Inc.) with 35% to 37% autologous plasma. Conventional PCs (n = 28) were gamma-inadiated irnmediately before transfusion (25 Gy; Gammacell 3OO0Elm, Nordion Interiational, Inc., Ottawa, Ontilio, Canada), PCs were stored up to 168 hours at 22 : 2'C under constant agitation in a flatbed PtLincubator (Helmer, Noblesville, IN). Bacterial testing was performed on all conventional PCs (BacT/ ALERT, bioMerieu, Inc., Marcll l'Etoile, France). The prepilauon methodofPCs uansfused was not inJluenced by the investigators. Palients All patients were treated accordinj ro the same institu. tional guidelinG with conventional intravenous cytarabine-basedchemotherapy,.andall developed severe chemotherapy-induced leukopenia with neutlophil comts below 0.5 x 1o'g/L.PLI tnnsfusions were.requested b], the patient's physician in accordance with international guidelines.3asProphylactic PLf trmsfusions were given to nonfebrile and clinically stable patients with periphera.lblood PLT comts below IOx10,/L and to febrile patients when PLI counts were below 20 x lOs/L In. patients with increased risk of bleeding (e.g,,befor€ invasive procedues or recent hemorrhage) or ongoirg bleeding, PLI transfusions wele adninisteled wtten peripheral b l o o d P L T c o u n t s w e r e .b e l w 2 0 x 1 0 e . t o 5 0 x l o r / L . . Patientswer; examined for human leukocwe antibodies O\ (FlowPRA Class I screening test, One iambda, Inc., O Canoga Park, CA) and human PLI antibodies.r6 Beticulated PLIs were enmined regularly and used for prediction of hematopoietic reconstitutiori.r? Investlgation procedure A sample was dnm by sterile procedures ftom the PCs immediately before Imnsfusion.,The following analyses were perfornied for characterization ofPC quality l) PLT dose,that is, number of CD6l+ PUfsin PC and CD6l+ PLT microputiclesr0 (CeU-Dyn CD4000,Abbott Laboratodes, RoundLake,IL); 2) metabolicwriables,that is,pH at 22'C, pCOr, HCO3, pO2, and concentrations of glucose and lactate (ABL 725, Radiometer Copenhagen, .Denmark; Modular, Hitachi High:TechnologiesCorp., Tokyo, Japm); 3) PLf density (mean Ptf component) concentration (Advia 120, Bayer HealthCarc, Tarrytom, NY); and 4) Iactate dehy&ogenase (LDH; Modulat, Hitachi HighTechnologiesCorp.),r8!e Prepantion method and storage time were registered for each PC. Blood smples from the study patients were collected through a cenua.l venous catheter before {<8 hr) transfu: sion,45 to 120 minutes afteruansfusion, and I8 to 24 hours after transfirsion for exmination df PLT couns (Cell-Dyn CD4000,Abbott Laboratories) and TEG tTEG hemostasis system 5000 series, Softwue Version 4.2, Haemoscope Corp., Niles. IL). For everystudy Eansfusion, the following Volume 50,Ap口12010 TRANSFuS:ON 767 APELSETH ET AL patient chtracteristis were evaluated:pretransfusion PLI count, bleeding, patient weight, fever at time of transfusion, infection (i.e., patient diagnosed with neuuopenic fevet treatment with antibiotics, md/or serum level of C-reactive protein > 100 mg/L the day oftransfusion), and treatment with steroids or griluloc!'te-colony stimulating factor (G-CSF).Jn addition white blood cell counts, medication, ABO and HLA compatibility of transfusion, occurrence of trmsfusion.compUcations, trmsfusion seqtience number, and ITI were registered lhroughout study period. Event charts including transfusion pattelns, reticulated PIX counrc,PLI couts, and duration of newropeniawere made for all patientgand treatment cyclesto serveas basis for interpretation of results, Methods for documentation of tlanstuslon effect Posttransfusion absolute PLI increment (API) is affected by quality and number of PUfs transfused, as well as the dilution of PLTsin the patient's blood volume. According to Europedn recommendations, we defined that m acceptable immediate API (at t hr afrer transfusion) occurred when PLf tmnsfusion iaised the PLI count above the tmnsfusion threshold, that is, greater than l0 x I0e/L.'3Toadiust for differences in PLf dose and blood volume of the patient, the corrected count increment (CCI) ms calculated by use of the formulae 20 C α= According to international guidelines, a successfi.rl lransfusion was defined as a CCI of more than 7.5 for immediate clinical effect (P!T recovery) and a CCI ofmore than 4.5 for late clinical effect (PLT survival).a,0 Body surface area was estimated by the formula of DuBois md DuBois.2l ITI was defined as hours ftom onset of study trmsfusion to the bnset ofthe subsequent transfusion.When the interal between tmnsfusioro was more than 240 hours, which is longer than the expected life span of transfused PLIs,22awe assuned that autologous PLT recovery had occued, and transfusions were excluded ftom- malysis. Bleedingassessmentsconsisting of physicalexmination and patient intewiew were performed each morning by trained nurses working at the \dmatologic ward.r? For additional clinical information, the medica.l records of the patients were consulted. The bleeding assessmentswere reviewed independently by two adjudicators and graded in accordance with the WHQ hemostatic asse$ments.rzIf disagreement occurred, the patient data were eva.luatedby a third adjudicator and consensus was achieved, WHO Grade of 2 or more was defined as primary bleeding endpoint according to recent PLI studies.r2'2''27 Accordingly therapeutic transfusions were defined as transfusions given to patients withWHO Grade 768 nANSFUSION Volume50,Apnl2010 MONrrORING PLATELET TRANSFuS:ON EFFICACY 2 or more bleedings before trunsfusion. The proportion of days withWHO Gmde 2 or more bleeding duing ndutropedia was ca.lculated.r3 To evaluateWHO bleeding assessments used for daily monitoring of PLT tmnsfusion effect, we calculated the diference in IVHO bleeding status before and after each umsfuslon. The blood coagulation processin patients before and after tralrsfusion was investigated by TEG in citrated kaolin samples with heparinasecups to avoid contamiia' tion of sample by heparin from the centml venous catlt. eter. The ,following variables were invesrigated: l) R, reaction time, the time to the begiming of clot formation, rcflecting the level of coagu.lationfacto6; 2) angle (o), the buildup and cross'linking of fibrin, dependent on suffr. cient amounts of fibrinogen, thrombin, and PLTs;and 3) MA, the mdimum amplitude, a measurement of milimum strength or stiffness of the developed clot, reflecting the amount and functiona.l capacity of PLTS including their interaction with fibrin.ta Referencelevels were provided by the manufacturcr. Statlstlcal analysis Eescdptive statistics were performed by use of computer software (SPSSi5.0 forWndows, SPSS,Chicago, IL) and resultsare presented as mean I standard deviauon (SD)if not otheruise stated. When anallzing PC characteristics not influenced by individual patient effect3,two-sample t testswere performed (SPSS,Ve6ion15.0).All patient data were malyzed, adjusted for individual patient efects. Analyses of dichotomous data were perfomed with generalized estimating equations (packagegee, R Version 2.8.0;http://w.R.project.org, The R Foundation for Statistical Computing, Viema, Austda), Correlation ana.lysis, not adjusted for individual patient effect, was performed by Spearman's correlation (SPSS,Version 15.0) due to partly categodcal data. Confidence interuals (CIs) were ca.lculatedas bootstrap BC. CIs (paikage boot, R Version 2.8.1,The R Foundation for StatisticalComputing).,3Differenceswere considered significant wheu p va.lueswere lessthan 0.05. To sepante the efects ofPC and patient variables on tmnsfusion outcome measues, mixed-effects model (packagenlme, RVersion 2.8.0,The R Foundation for Statistica.lComputing) was performed,2s.3o If random parts of the mixed-etrects model were unstable, genera.lizedleast were.used. squares In this analysis we invesugatdd the relationship between posttnnsfusion va.lues of PLI posttransfusion costs, TEG values, arid ITI and the following variables: fever, transfusion sequence numbet padent weight, bleeding ofWHO Gmde 2 or more, PLT dose,storagetime, prepilation technique, and ABO identiry AnalysesofPL;f counts and TEG valueswere adjusted for time and pretransfusion values. The selection of variables investigated was based on previously published drticles,:s'st're md the number of vuiables was adapted to the total number of study transfirslons. Mixed-efects analysiscould notbeperformed for bleeding status due to the.categoricalnatute of the variable. RESULTS PatlentsandPC8 Ten patients, four males and six females, djagnosed with .acute myelogenous leukemia (eight patients) or acute lymphoblastic leulemia (two patients), were included in the study.Transfusioii requirements were folJowedby the investigators from the administration of chemotherapy (five remission induction and eight consolidation treatment cycles) to hematopoietic reconstitution (i.e., >0.5 x to'g/Lneutrophil granuloc)'tesin blood samples and noneedforPLf tlansfusion), patientwithdmwal (two patients), or death Of patient (one patient, due to infec. tion). All patients (ages2l-62 yeals) had a history of previous pregnanciesand/or previous PLI tmnsfusions, but no patient with previous splenectomy or disseminated inttavascular coagulation was included in the study Patients with HLA antibodies were transfused with HLA Class l-matched PCs (three patients) according to international guidelines.eOne patient was diagnosed with weak positive HPA utibody at the time of inclusion dnd transfused according to routine practice without HPAmatched PCs. No padent developed HLA or HPA antibodies during the study. All tmnsfusions were AB0 compatible, by means of recipient having no antibodies incompatible with the red blood. cell qpe of dontir. Qne patient was diagnosed with neutropenic septicemia. These transfusions (four) were grouped and malyzed together-withthe transfusions giwn to pdtients with infec. tion. In I1 uansfusions, patients received ueatment with hematopoietic growih factors, Threaof these uansfusions were given to acute lymphoblasric leukemia patients treated according to the H'?er-CVAD regimen and eighi transfusionsto acute niyelogenous leukemia patients due to severebacterial infections. The mean PLI dose given was 2.79 (Iange, 1,46-4.42)x 10r! per unit, and mean storagetime ofthe PCwas 86 (range,2l-167)hours.The metabolic status of the PC was as follows (m€an t SD): pH (22'C)7.22! 0.I4, pCO, 2.98 t 0.47kPa, pO, 17.3t 2.1kPa, glucoseconcenuation 5.18 I 1.55mmol/L, and lactateconcentration7.35 1 3.64 mmol/L. The LDH concenuadon was 135 (rmge, 2l-522) UlL, and.the mean level of PUI micrgparticles was 26 (range, 6.750.6)x lo'g/L. Effect ot PLT transfusion PLT viability PIII viability was eva.luatedby PLI count increments and calculation of ITI. PLf transfusion increased peripheral blood. PUf counts after'both I hour (mean increasei, x 10,/L) and l8 to 24 12,5x 10,/L 95% QI, lO.0x l0r-1i1.9. hous (mem increase, 7.2x1.0e/L; 957o CI, 4.7xlo'g9.7xlo'g/L). Significant correlations were observed between pre- and positransfusion patient PLI counts ( a f t e r l h r , r = 0 . 5 6 9 , p < 0 . 0 0 1 . ;a f t e r 2 4 h r , r = 0 . 4 5 7 , p ; 0.005). Forty-six percent of PLI transfusions raised the patients'immediate PLI counts above the trmsfusion threshold, that is, more than 10 x lo'g/Li and were thN defined as acceptable according to tlie European recom. mendations.e When evaluating Pllt viability by use of CCIS,46% ofthe studytnnsfusions were classifie! m suc. cessfirl after I hou, whereas 5370of uansfusions fulfi.lled predefined criteria after 24 hours. Eight out of l0 patients received more than.one transfusion per treatment cycle, and all of them experienced both successfultransfusions and transfusion failures (Fig. l). The results of compaative analysisofpatient and PC.characteristicsin successful transfusions and transfusion failuies are reponed in Table l. When evaluated by immediate response,the suc. cessfulPLT trmsfusions were differentiated ftom transfu. sion failues by superior PLf quality (Table l). In contmst, successful PLI transfusions evaluated bi late response showed favorable patient chamcteristics.Mean ITI was 4l (rante, 7- l2I) hours, and there was no significantly highe! ^ ITI in PLI tnnsfusions characterizedas successfulby CCIs ! after either I or 24 hours. -l PLT tunctionality Eight patients experiened minor bleedings (petechiae and minor nosebleed), giving a total of 34 days (18.0%) withWHO Grade I bleedings during the total studypdriod (188 patjent-days). Only four patients experienced WHO Grade 2 or 3 bleeds, giving proportions of 7.4 and 2.1% of total padent-days, respectively.The time to frrst bleeding (WHO Gnde > 2) varied between I and 15 days and the individual proFiortion of days with Grade 2 or 3 bleeds varied from 6.3% to 66.77ofor ihe affectedpatients (Fig. 1), . No WHO Glade 4 bleed was obserued during the study period. The bleeding event chart did ,not indicate any associationbetween time to the nrst bleed and individual number of bleeds; rather, it did illustrate the individual differences in bleeding pattern among patients with the similar diagnosis and PLI counts (Fig. l). In spite ofhigh frequency of PLI transfusions, bleedings still occured, and patients with the simllar morning PLI counts d.idnot experience the sme number, timing, and sevelity of bleeding. Significant correlations were observed between l) WHO bleeding status before and after transfusion (r=0.639, p<0.001) and 2) WHO bleeding status after timstusion md ITI (r = -0.380, p = 0.020). No significant correlation was obseryed betwegn pretransfusion PUI comts and bleeding a3sessmentbefore and 24 hours after transfusion, neither was anv condlation obsi:rved Volume 50,Ap112010 TRANSFuS10N 769 MON:TORING PLATELET TRANSFuS:ON EFFICACY APELSETH ET AL, ing of R, increased angle, or MA incte'ment after PLf transfusion when evaluated by correlation analysis. 770 IFANSFUSION VolumeSO,lprtt ZOtO 7(41) 12(71) 4(24) AB01dOnJcal transrlsion Stora9o lrn。 (hrl 101'per uno PLT dose(× PLT concenlralon(x100/L) V●りm,(mり C(mttH9) pH a1 22° pC02(kPa) ￨ m。 Ll HCOo(口 レ p02(kPa) L) 01uCOSO(市“。レ Laclale(mm01几) ne→0 需 :1胎 :「 需認品ぽP° 0 た し OH(Uパ ⇒ 8(4ηl 14(82)t iO(59)十 3(15) 11(551 9(45) 13(65) 106=45‡ 281=065 7 1 7 ±0 1 2 ‡ 2181 =037‡ 50=15‡ 45=15キ 89■ 351 192=08辛 12(63) 12(71) 307 ±062‡ 970=203 318■ 33 64■ 116 52亡 17 65=34 297=048 57■10 54=1,4 8 4 ■3 9 25■ 12 3 0 ±1 0 ‡ 25± 10 162=lo9‡ 103=64 ' Flesullsarg prGenlsd as number (%).or mean : SO. t p < O.O5lor dlfier€ncb bstween suc€sful ancl nonsuccossfullransfusions(lest tor dichotomousdala adiustod for lndividualpati€nl ettecl ,Rl) l g● ● ‡p く0 0 5 f o r d rerence belween s u c c o s sn ls ur uO aЫ mpbs,SPSS n ns d l l ot ne sS ul cf cO ord se smn ldt ue lpS lOa に Ⅲ 16 0). When evaluated after 24 hous, correlatiors were obserued between PLT count increments and fever, trmsfusion 11 1 43=11 17 47■ BofOre transFusion 82■ seqirencenumber, and pathoged inacti8+ 52=9+ l hr arler trahstusiOn 68■16+ 58± vation. No significmt correladon was 10+ 18 50± 24 hr anortransrudo口87■ 0 49■ obserued between ITIS and the patient ' Tesl lar continuguEdata adjusled lor pati€nt eftect (packagg nhe, R). Results are pr€or PC variables investigated. Similady, s€'ntedas heil : SD. n = 33. I p < 0.05 for difigrence between postlranslusionand pGtfansfusionvaluel no significmt corelation was observed between the PLI functionaliry measure bleeding ouicome and the investlgated patient and PC variables.No couelation was obsewed for at time of trmsfusion experienced a mean rcduction of the TEG values R and angle, while a negative correlation the ITI by 39% compared to nonfebrile patients (Table4). was.obseryed between MA increment after 24 hous and The mean ITI was 27 t I hours in febrile transfusionsand patient weight (Table6). In summary, the results ofcorre46 t 30 hous in nonfebrile transfusrons. lation analysis show that PLl-related factors maidy influ' Whereasthe selected patient or PC variables showed ence the immediate clinical effect of PlI tresfusions, significmtinfluence on the measurementsof PIjrviability (PLI count increments and ITI), no significant influence whereas patient-related factors influence late clinical wm observi:d on PlI functionality measured by TEG. effect. Mixed-effects analysis could not be pedormed for bleedingstatus. DtscusstoN Conelation analysis of vatiabtes influencing effact o( PLT ttansfusion Spearman'scorrelation analysis was pedormed to separare between variables inJluencing immediate ild late clinical'outcomeof PIjt transfusion.The ma.lysisincluded bleeding outcomes ud was not adjusted for individua.l patient effect. The immediate clinical effect of PLI tiansfusion elaluated by measurements of PLT viability (PLT count indrements) showed strcng correlations to PLI dose, storagetime, md pathogen inactiwtion by PCT (Table6). In this study we aimed to evaluate and compare methods used for documentation of clinlcal effrcacy of PLT trmsfusions in patients receiving regular PLI transfusions due to severe chemotherapy-i.nduced thromboc'4openia Our results illusuate the advmtages and dlsadvmtages of the different methods when used for documentation of clinical efiect ofrtigularPLl transfusions.The challengesidendfied ae discussedbelow. By statistical analysis of 40 PUI transfusions we, observed that PLT vi4bility Ms affected by both patient. and PC-related variables. The vdiables identified in our Volum● 50,Ap市12010 TRANsFuS:ON 771 ＨＯＨ .Variables influencing eftect of FLt ltanstuspn The effect of PLI uansfusion varies n g . 1 . T h e b l e e d h g e v e n t c h a r t d iOs pClraaydse W2■ o r h i g h e r b l e e d i n g s , P L T between individual uansfusions within transfus:ons,and mOr●ing PLT∞ unt during neutroptnia fOr each patient and treat・patient and ueatment cycle, but also ed: r i n g:● ct」 o F 1 8 8 Pean● t d a y 5 , a t O t a l o f W 5e 2r e b lr ee ep do ir nt び m e n t c y.cDlu● between patients. The analysis of vari34 mmor bleeds(WHO Crade l)and 18 clmicdlysuttncant 11,eds(14WI10 Crade 2 .ables influencing outcome of PLI ●nd FourWHO Crad● 3).The bleeding ewnt chart llustrates the mdivldual dttr‐ tmnsfusion was therefore adjusted for bleedhg patterll arn,ng patients with ule simuar diagnosis and PLT counts, ences I● .indivjdual patient efect. We found nt uthdFawals(Patients 2b and 9)and one death Durlng thestudy period two patた that the selected patient variables C Curred. 餞 tent 10)。 (ransfusion number, sequence bleeding > WHO Grade 2, fever, and patient weigho and PC vsiables (storagetime, PLI dose, between PLI cout increments ud change in clinical prepdation technique, and ABO identiry) influenced the bleeding status after transfusion. When ialcu.lating the different methods for documentatiom of tlmsfusion difference in WHO bleeding status before and after trans'fusion, no effect ofPLfuansfusion was obseruedeither for effect differently (Iable 4). Elevatidn of PLI dose by I x lotr per unit led to a the total of trmsfusions (mean t SD,-0.03 1 0.73)nor for mean increase' in posttransfusion PLI count by the seven therapeutic uan!fusions when andlzed sepa3.2xloslL, whereas prolonged storage time"(by I hr) ot rately (meil I SD,0.14 t l.0l). pathogen inacti%tioq by photochemica.l treatment The overall results of investigations by the TEG mareduced the postuansfusion PLI count by 0.04x loe and llzer ile reported in Table 2. PlI transfusion had an 3.9 x 1O'3/L respectivel)a Corrdspondingly prolonged imm€diate but transient efrect on initial clot formation storage tine or pathogen inactivation reduced CCI by thai was reflected in the R and angle variables, whereas 0.02xmzlL and 1.7 PLiIsx m?/L respectively.Additional the efrect on PUf clot strength and stability, the MA value, investigations showed reduced PtI dose and qualiry in persisteduntil the next day.No effectwas obseruedon PLI pathogen inactivated PCs (Iable 5). Patientsbeing fdbrile dose or the number ofPUT micropdticles on Oe shortenL●oponla 0●●椰いn● rtient vailables FevBa ぃrec10n C・CSF PLT Va"abbs ３ ２ ０６ｍ３１爛０︲９０９２６ 051015202530 CCl afto7'hr ８２ ９０ ３０ ２油″８ ︲蜘調７ ︲５ ５ ２ ﹁２ ７ ７６ ︲ ９３ ︲ How do the methods monitoilng clinbal eftect of PLT transfusion intercorrelate? Coirelation analysesof the investigated methods for documentation of PlI transfusion were performed, and the resu.ltsare pr€sented in Table3. Strong correlations were obseryedbetween the methods based on PLt counts (API,CCI, ITf, and MA) when us6d for evaluadon of transfusion efects after both I hour and 24 hours.A negativi:correlationwas observed between the increase in MA after 24 hours ud the calculated difference in. bleeding status after tansfusion. Correspondingly, a negadve correlation was obsened between MA increment after 24 hours and clinical bleeding status after tmsfusion (r=-0.494, p=0.00S). No corelation ws obseNed between PLf count increments and calcrilated d.ifference ur bleeding status or clinica.l bleeding statris before or aftei transfusion. TABLE 1. Characterlsticsof successful lranstusiona versus transfusion tallur6s' MON:TOR:NG PLATELET TRANSFuS!oN EFFICACγ APELSETH ET AL. TABLE 3,'Correlalion of m8thods for documentatlon ot trrnsfusion eftectr Ы Onoutomem:“ uにc。 龍博 翻1::R:よ よ 艦n:e畔 湘 2■1悧 器P鴇譜齢野暑淵蹄 ■,ゴ Ч 0308 05491 05181 ︲ ２ ４ ２ ２ ５ ” １ ６ ０ ０ 09181 09521 ０ Ю 。 ↓ ０ ０ API Afl6r t hr Afior 24 hr CCI i Aft€r t hr Aft6r 24 hr Transfuslon inleryal (h4 Aft€rlhr-' Aftor 24 hr 24 hr posttransfugiondiFference in WHO bleedlng grads After t hr Afler 24 hr Posttranglusionditfsrence in TEG values R (min) 'l AftEr hr Atlat 24 hl Angle (degree) Aft€r t hr AftEr 24 hr 匈 406‡ 0109 Ю 33tl 0052 0.5971 04601 04031 0155 o 410t 0 4401 0173 0427幸 “458‡ 0001 0263 -03821 -0362+ 0038+ ■ ´ 0100 0015 : 04o5+ 0032 transfusions with lower PLI dose,33A of bleeds defined as or higher and higher .Transfusion outcome moasuro p valu€ Moan ditferonce 95o/.Cl number of tansfusions has previously APl(x10° /L).市=40 been described in patients being uansPLT doso(by l x 10'po7 un→ 32 03to61 0 030 fused rjvithlow-dose PCs.t'?Themaiority Oocreased APL of ou study transfusiorls (28 of 40) Stqrage umo(per hrl would have been defined as low-dose -39 -741o-05 0o27 Pathogen inaclivatbn by PCT(yOS) OCI(PLTs x P/L).n=40 uansfusions according to this publicaDecreased Ccl tion, and a low rmge of .PLTdose may Slorago,me(per hう 002 “ 05 toつ 00 0041 . ‐ therefoie explain why no conelation Palhogen haclivatbn by PCT lyOSl -17 ⊇ 71o06 0003 TranstuЫ on hterveL n.37 wm obserueil between PLT dose and ・ /.Reductbn bleeding in our study. Fever(yOS1 39 14 1● 5フ O oo8 Outcome measures based on Analyzed by mixed'gtfects model (packag€ nlm€. R). bleeding are complex becausethe clinical impact ofbleedings depend both on severity and on location. A calculation study de in accordance with previous publications.'z3J-36 ofdifference inWHO bleeding status before and after each Evaluated by measures of PLT viability, PLI recovery was tlmsfu sion implies treating bleeding as a continuous vadinfluenced by PC vuiables only, whereas PLf suryival was able, which it is not. The use of bleeding asessments in influenced mainlyby patient vuiables. Being a retrospecthe evaluation of clinical effect of PLI trarofusion theretive variable, the importance of calculated ITI in daily fore requires a different approach. Webert and colpatients monitodng of thlombocltopenic is limited. It is leagues2?have shoM that minor bleedings (WHO Grade l) predict clinical significant ble€dings (NHO Grade 2, 3, also dependent on the individual umsfusion uigger chosen for each patient, which makes comparisons or4) md that cumulative incidence furictions forbleeding (Grade l, 2, 3, or 4) increaseswith tine. Correspondingly, between patimts di.fficnlt. we obsbrved that the WHO blgediirg status before and PUI dose may influence both API and the calcu.lated CCIs. As shom in ou study, higher PLT dose may be after umsfusion was correlated. Webert and colleagues, obsewed in transfuslons with lower CCIS.As discussedin howeve! found that the risk factors for mild bleeding a previous publication, this obseryation may be e:iplairied included decreasedPLI count, an associationthatMs not by the formula for calculation of CCI, which favors PLI connrmedby our obseryations..Inour 40 transfusions,we 私B L E P●m に 耐a n d : Я m ソh ・ uen.e● d m ● higher nmber 轟: 害 路 掘湘 肝 WHO Grade 2 7f2 TRANSFUSIONVolume50, Apdl2010 Conv€ntionalgamma.iradialgd J v a byi'■ cl anOr l h「 ccl aro(lh′ Cl aner 24 hr CCl amr24 hr Transfusion interVal(h0 PLT valabl● s十 Storage umo(hrl PLT dose(x100 per unll pH at 22'C(mmHg) pC02(kPa) HCOo(mmOνLl p02(kPa) LDH(υた) Pathogen inaclvatod(PCη PCs h‐12 53=2,7 2 ■6 1 8 ±4 4 36=24 8 6 ■4 6 296t063 726=013 311■ 039 66=13 lo 6=18 96± 67 01005 0196 0890 0360 86■ 4o 241 ■ 0,46 713=010 266=050 . 43=12 190=17 . 224■ 148 1 0973 0009 0004 0004 0001 く く 0001 0014 ' Tesl lor@nlinuous dala adjuslod tor palionl €lfect (package nlmo, R), t I lesl lor trc Independ€ntsanples (SPSS). TABLE 6.patlent end PC va‖ Iransfusion out@me d€6ure Couelation @'fliblent 95% Cl ,j :濶二■ 1■ 1童 歓 R「 A贔 ￨:議 I鍛 濯 「1 Fover i . ‐-0386 : 1`38 -0 631 to 0 0'4 Translu゛ on soquence number Palh● 99n inamvttbn ccl aner 24 hr(PLTs x m2/L) ittuti:n轟 」 .n■ limb::1 Mfl:器 :II:譜 1,Irttm _0392 _o406 6541o‐0048 6520→ 050 ● “ ' i J51 匈1,:゛ ‐ 1:1挙 11 .I::::Bl:説 ° 03γ l l 「 oΨ° : :° Palent welohtt i -0439 -07o9tO o 019 ・Analyzod bソSpeamallt● ●7701atた n(SPSS 130)and b001strap BC.Ci ca c11■ loO(B) obseryed no sigrdficant correlation between pietnnsfusion PLI cqunrc and bleediag assessmentbefore md 24 hous after trffifusion, neitler wro any correlation obsewed between Plf count increments.md change in clinical bleeding status after transfusion. This observation correspondsto the results of Friedmann md coworkels3s who fqund no relationship between the lowest PLI count of the day and the risk of hemorrhage when investigating 2942 patients over a period of 10 yetrs. These difrerences in conclusionsmaybe explainedbyinconsistentreporting of bleeds (i.e., problems with sepilation of new and ongoing bleeds) or individua.l diferences in grading and interpretation of bleeds by adjudicators, yet the discrep: ancy strongly indicates that rhe present bleeding ssess. ment schemedoes not provide the information needed to serye as documentation of clinical efiect of PLI trlusfusion. In accordance with Heddle and colleaguesu we thereforerecommend a reevaluation ofthe present bleeding assessment scheme, p value ０呻 叫¨¨ ｍけゆ・¨・ 叫 ¨０ ︲ ・ ・Resu,s shOwn as correlaJon coofnc10nt(Spearmanヽ c。「 701ation,SPSS l'0).● ■40 1 Correlation is signllcant at the O ol 10vel i COrre atbnにdgnmcan a mo o o5 bvel 03621 0306・ TABLE5. PLT vlabllitv 8nd iranstuslon charactsrlsllcs Dresentedaccordlnq to DreDaratlontechnlouea Transfusionoul@m€ m€surE and variabl€s , 0019 ' As indlvidual patient and PC variables inlluence the methods for documentation and: clinjcal evaluation of umsfusion differently, a direct omparison between tansfusion outcome measures was difrcult to perform. By Correlation analyses,however,we found no consistent correlation between measures of PLT viability and functionality. The strongest correlations.wereobseryed wlthin measurements of PLT viability md between PLI count incrcments and MA, which reflects PLI pmber as welJ as functiona.lity of PLTS,A negative correlation was, howeve!, obsewed between clinical bleeding status and late MA inclement, indicating that a higb MA increment ma)abe associatedwith less clinical bleeding. A previous publicatjon repons that nonactivated tfuomboelastography ms sufficiently sensitive tb monitor changes after PLI transfusion in patientswith severeto mild thrombocytopenia.s? Oui observations confirm that the efrect of PLT transfusion can be visualized by teG analysis,but by sbowing an association to clinical bleeding status they also indicate VOlum● 50,Ap"12010 TRANSFuS10N 73 MON:TOR:NC PLATELET TRANSFuS10N EFHCACV APELSETH ET AL. thatTEG maybe a potentially useful surrogate measure of PIJI tunctionaiity. Based on ow observations we conclude that further investigations and standardization ofmethods are needed for better documentation ofPLI transfusion outcome and identification of patients at risk ofbleeding. Our obseruations also indicate that both PUt dose and high quality of PC are important for achieving m optimal immediate response to PLI $ansfusions whereas duration oftransfirsion effect is influenced mainly by patient variables. Heddle NM, Blajchmu MA, Meyer RM, Lipton IH, walker granulocyte utigens McFarland IG. Platelet ild and anti- Thorpe !G, Lwine MN. A landomized controlled trial comparing the frequency ofacute reactions to pl6ma- Bethesda: American A3sociation of Blood Banks; 2008. p, 29, 30. Pinheiro IC. Mixed-efects models in S and S-plus. lst ed. removed plateleb and prestorage ltBC'reduced platelets. ,l .i DuBois D, DuBois EF. A fomda Ttansfu sion 2002;42r556-66. mate surface aea lf height and weight be knoM. Arch Snyder E, Mccuuough L Slichter SL Strauss RG, Lopez Inrern Med l9i6;17:863-71. Plea I, lin ,S, Corash L, Conlan MG. clinical safety of platelets photochemically trealed with amotosalen HCI Hanson SR, Slichter SI. Platelet kinetics in patients wiri bone muwhypoplasia: ud uluaviolet A light for pathogen inacrivation: the requirement. Blood 1985;66:II05-9, SPRINT trial. Tlanstusion 2005r45:1864-75. to stimate the approd- 32. Slichte! SJ, Davls K Enright H, Braine H, Gernsheimer T, Heim D, Passwegt, Glegor M, Buser A, Theocharides A, Arber C, Meyer.Monild S, Halter L Ticheli A, GnMohl A. Patient-and product factors affecting platelet transfusion resulrs. Transfusion 2008;48:58I.7. Cid ,, Rmiro L, Escoda L, LlorenteA. Efficacy of.trasfusion of platelet concertrales obtained by manual pooling sion platelel incrments, platelet reftactoriness, md plarelet tnnsfusion intervals in thrombocyropenic patlents. ' l. 2. ' sion platelet response: problems ud sion I999i39:586-92. ment and transfusion iDterval. Vox Sog 2009;96:29-33. Rebulla P. A miDi-review on platelet refractorinss. !lae- 2004;18:153.67. 3. A, Kououkis CT, HeryigT, Klappe! E, Brandwein JM, Szsepiorkowski ZM, AuBuchon ,P, Barry RL Lee KA A randomized conlrolled trial com. Strauss RG, Goodnough LT, Fridey JL, Raif€ T, Cable R, Murphy S,{owpd F 4th, Davis K, Lin lS, Metzel P, Corash paring standard. and low-dose strategies for tr4nsfusion of platelets (SToP)to patients with thtombocytopeni4. Blood L, Koutsoukos A Lin L, Buchholz DH, Conlan MG. Therapeutic emcacy and safety of platelets treated with a photo- 2009iI I3i I 564-73, chenical proce$ for pathogen inactivation: the SPRINT Cook RJ, Heddle NM, Rebulla P. Sigouin CS, webert KE. Trial. Blood 2004;104i1534-41. Methods for the malysis of bleeding outcoms Tinmouth A, Tilnock in rildom- SJ, Hyde C, Heddle N, Rebulla P, Bruskill S, MF. hophylacdc platelet tlansfusion for haemor- utibodies Cochrane Databse S)st Rry 2004;(4):CD004269. 2005;45:I3t9-23: IL RE, Poweu BL, Rainey IM, Rowley SD, Rebulla P, disorders, pue erytluocytosis, reactive thrcmbocltosis 37. Salaj P, Mdingv I, Makova M, Pohlreich D, Cettorskt P, Hlachovinovd L Thlombelastography monitoring of plarelet substitution thelapy and TFVIIa administratlon in haemato-oncologica.l padents with sev€E thlomboc''tope' nia. PragueMed R€p 2004;105131I.7.d morherapy, Platelets 2006;17:296-302. cetrtrates dudng storage platelet counts and markers of MF. New srategies for the optimal use of platelet trusfusions. plateler deslruction. llatrsfus Apher Sci 2007;37;261-8. Apelserh TO, Brserud O, WenEel-t2reen T, Bakken AM, Soc Hematol Educ Program 2008;2008r Bjorsvik S, Heryig T. In vitro evaluation ofmetabolic change od residua.lplatelet Esponsiveness ln photo- 198-204. Blajchman MA, Goldman M. Bacterial contamimtibn platelet concentrats: incidence, significance, ild tion. Semin Hematol 2001;38(4 Suppl 1t):20.6. TBANSFUSION patients? A reevaluation of prophylactic platelet tresfu. and Apelseth T0, Hervig T. In vitro evaluation of platelet cori- HematologyArr FriedmanDAM, Sengul H, Lehmann H, Schwartz C, Ryntngen,tL Apelseth T, Hausken T, Bruserud O. Reticulated platelets de iDcreased in chronic myeloproliferative cal Oncology. Plstelet transfusion for patients with cancer clinical pEctice guidelines oftheAmerican Society of MA, Slichter SL Heddle NM, Muphy 36. with the monoclonal antibody prior to hematopoietic reconstitution after intensive che- Blajcbma laboratory factors thar affect rhe posrtransfusion plalelet increment, TtaDsfus Sci 2OO0;23:63.8, of platelet atrtigens procedure. Transfu sion Tloner MB, Wagnon AH, for theAmerican Society ofCltn! Clinical Oncology. I Clin Oncol 200I;19:1519-38. 7'4 otigen-la immobillatior M, Goldstein M, Hume H, Mccullough A. Clinical od Beitrmd G, Jallu V Gouet M, Kiaer !3\,1,Lambin P, Husebekk,4" Kaplm C, Quantification of human platelet rhage after chemotherapy and stem cell transplantation. Schtffer CA, Anderson KC, Bennett CL Bernstein S, Elfing leukemia: a rudomized myeloid leukehia. Haematologica 2006;91:1530-7. p. 149-60, 2006;lO8:32I0-5. 35.. Fabris F, Soini B, Saltod R, Randi ML, Luzatto G, Girolmi Volumo 50i ADril 2010 of prcven- chemical treat€d od C) sions. Tlansfus Med Rev 2002;I6:34-45. Webert K, Cook RL Sigouin CS, Rebula P, Heddle NM. The risk of-bleeding in tfuombocytopenic patients with acute nents. Strasbourg: Council ofEuope;2008. domired study of the efrcacy of transfusions with platelets stored i! platelet additive solution I vercus plasma. Blood Iet uansfusionsin recipients ofa autologous peripheral blood progenitor cell transplet and patients with acute Euopean Commilte on Blood Ttansfusion. Guid€ to preparation, use and quality assulece of blood compo- Mclntfe 5, S, The sur- Kerkhoffs IL, Eikenboom IC, Schipperus MS, vanWordragen-Vlaswinlel Rl, Brod R, Hryey MS, de-Vris RR. Bdge R, van-RhenenDL Brand.d A multicenter ran- O Goodman S. Do basic laboratory tests or clinical obserya" r{ rions predict bleeding tn rhromboclropenic oncology with acute leulemia, N Engl / Med l I.s, Goldsmith 5. Dickinson KL Ttoxler M, Home!-Vamlasinkam a solution. Ttangfu- lF; Crump M, Tomlinson c, BEndi wein L Minden M, Sutton D. Lw.dose prophylactic plate- controued trial wirh a squential Bayesian desig[ Transfusion 2004;44:l 7l I -9. Muphy 4. A. Snyder E, Stadtmauer EA, bpez Plaa I, Coutre S, function tsting. Br t Sulg 2008;95:1317-30. Srdworth 34. Mccutlough t, V6de DH, Beniamin Rr, sljcbte! Sr, Pineda matologica2005i90i247'53. gical application of pojnt-of:cale haemostasis and platelet Haematol 1978;7:523-39. Davis KB, Slichter SJ, Corash L. Corrected count increment andpercent plitelet rccovery as measws of posttlmsfu- Blood 2005;105:4106-14. Gaydos IA, Fteireich E , Mantel N. The quantitative rela. tionbeMeen platelet cout ud hemonhage in patients 2;266:905-9, 33. Slichter SI. Relationship between platelet count md bleed" ing risk in thomboc]4openic patients, Tlansfus Med Rw count incre- 1135-42. Slichter SI, Harker lA. Thrombocyopeniai mechanjsms and management of defecrs in platelet productioq. Clin transfusion.Ttansfusion l99l;3 l:3S2-6, tive ualysis of counl increment, m[ected Heddle NM, Cook Rl, TiMouth l4 IP, Mccrarh K, Yuen K, Wolf MM, S@r I. Factors influencing 2p-how increments afrer platelet or by semiautomated pooling ofbuffy-coats: a retrospec- ized trials ofPLT transfusion triggers. Tiansfusion 2004;44: REFERENCES NewYork: Springer; 2000. p. l-270 evidence fora fixed platelet WeappEciatethepatienceudhelpfulness shoubythe nunesat the Sectionof Hematology, Deparrmentof Medicine,Haulrcland durlngthe couectionof patientsamplesand UniversityHospita.l, daily bleedingassessments includedLothis work.Wealsothek SolfridBjorsvtkand LindaSkordalat the BloodBank,Haukelud Univelsity Hospitai,for technicalhelp and assistan@with the tfuomboelastogtaph ana.lysisand Kristin Paulsen md Aina Kvinnslandat the Inctituteof Medicine,UniversityofBergen,fo! technicalassistucein measurements of ieticrtatedplatelets. l3 with R. lst ed. NewYorkl Bishop IF, Matths Kao Kt, Kicklbr T, I€e E, McFdland J, Mccullough L Rodey G, Schifer CA, Woodson R. Factoc affecting posttransfu- Br J Haema- Dalgaard P. IntloductorystatistiG Springer; 2002. p. I -267. 31. rol 2003;l2ztlo-23. CONFUCTOF INTEREST NewYorkr Chapman& Ha.ll; 1993. 525-40. ACKNOWLEDGMENTS The authorsdeclarethat they have no @nfuctsof inrerestrelerut to the manuscliptsubmiiledto TMNSIUSION, Efron B, TibshiEni RI. Ati introduction to the boorstrap. bodies. la: Roback ID, editor. Technical manual. Guidelines for the use of platelet lrasfusions. ll 28. IR, Sher GD, Constantini l"A, Pattelson B, Roberts RS, gamma-inadiated single-donor platelet concentrat6 duing long-tem stonge, Tlansfusion 2007;47:653.65. Volum650.ADril2OlO TRANSFUSION75 配布にっき、FDAの ア解済み。 資料 6-4 curront FDA ConsidoratiOns OglenlRlediuction 0,Patい ‖ ″ :ま 1に 鷲1黒 高,よ 4町 :1:l♀ 巽 礼￨: ・ 針 n,soT' 0'n‐ 甲 'uず lい 'aγ :躙講錨課 甲 n,9thlr",9 relatede agl。 Vё en16 _ ■Mayprevent 9VHPち ● DisadVantages Jaro V6stll:MD,Pぃ D I‐ ‐ ay Epstein,MD‐ 1 」 C6rter for)liOlogiё VIlua‖ 6高aぃ l Ё 0 16search U.o,F99o and:Drug AdttiniStrauon(FDA) september 2010 , ￨ ￨ ‐ ‐t i善 n'￨■ ]翠 ギ 1鮮布 警黎ギ ■ 尋 :キ 。 11・ :祗 謂Tmlす 灘懺肌]:運 ‐ ξ gよ i潜 ￨‐ 孵灘 出轡蜘 ヾ〇出 配布につき、FDAの 7解 済み。 Me面ts ofthe Current Approach Of D6nor sCreen■ g and ttosl19 ‐ AdvantagO■ ‐ . 1 ‐ 。N O t 6 x i C ity loSues for reCiplents of prOduё ts ‐ : D ёt e c l o n is specinc for panicular agelts‐ ￨ ' Itttκ Velal,eT'「 。 早 」 t'd'Can b9 de半 :￨:ledP「 ling 3:‖ DiSadvantages ‐ ‐ ・For certain pathOgens detection iS not 1000/。 succeSSful ― Bactetta l―Protozoa 二 viral(windoW pettod) . . 1離鯉翻:樹 Ⅲr‐ 郡 :1営 O Add託 ionaltests rgiho for emё latい 。 cost‐ gohs incllasё ` ‐ ‐ 配 布につき、F O A の 了解済み 。 isOry endaloh ofthe dψ HHSハ IR90om商 「￨ '躍庁亀:胤瀾留1鍍 l認 8reACB,Ar,:ITT' 冦 1常 備皐11:1:鑑 譜 "ヽ 鷹￨::ど 眉鋸膳 梶11:∬ 譜:讐 電l:::T電 ￨ き、 FDAのア解済み, 熙市IFう E'rt't:?*. FDAO7ft*rl" Bёnё fits Of Pat,hooen Red1011 prlduこ ts RIskS I i ShOuld Outweigh thё BeneFltニ Reductibn 6f CirFent risks: ・HTLV 1/2,993,000 ￨ ‐ I Red CeH Products ‐ cc,「 us s3o3 and Vitex len llo . ｀ O Patients deve10ped antlbOdiё S tO trё ated rod celll , Botli sponsors vOIlntarily haltё d their trials ・HⅣ ・ HCV 1/2,135,000 1/1,93o;000 ・WNV 1/ 350;000 ・ HBV 1/ 277,000 ,Sepsis 1/ ‐86;0001 Reductibll of futi‐ re riSks: ・ Emcrgittg path9gens 1/????? TolerableRisk Toxiciry adversegvents shouldbe much less thanthe expectedbenefits << l/86.000 Phase l‖ Clinical THals OF し nPatぃ Red‐ 。 oed gё ▲ ‐‐ Beni9口 」 ・ ,llBtt sCienoe eS(2006)1.222,226 se‖ ",:R・ 1)EdёL A.F etal.Transfusion 2009,49:1554‐ 1563 ｎｏ出 : 布につき、FDAの 了解済み 。 配 配 布 につ き、FDAの ア解 済 み 。 DeterFnination Of the tssoё Risksメ i ated l196dIC6品 Rё "ith Pathogen‐ pOnenisl , Pre_cllhical eval画 atiOn l l l d patientS ‐ c‖nical trials in tFan,fulё ニー ￨‐ p rOspective,randOrnlzed,blindedi clihical trials1 0f i ,Platelets ‐ ・ ・Red cells Plasma al transfusipn,pFOduCtS li ‐ safety10f a Platelё t TranSfusioh lPrOdし ct Effi109y: l ・Cliハ iCal tHIIも in heLた hゾv611ntё lrs l . PiVOtalalり eヤ a」 on of 91Ca9y andtysaゃ thr61gh PR tr9111o vS,COnvenloぃ 91iⅢ 1091 E,dpQints thlt ttelect Effi I‐ ‐ ■TransfuS10口 Crement, 「 Olntぃ lspOns6(cO「 "d ё 「 9ё (CCり ヽ ￨ ￨ 9y ■■￨￨lfusbhrfrequen‐ ・‐ ё quenCy(Crades 2,4) ￨.: lleeding F「 、 ￨ 1 ‐ SIやty. ￨■:Adversёevёnts ■A I 1 0 i m m u n i z a J o n I ‐ :￨ ￨ ￨・ 「■ ￨ CI:nical THall of pRlё tplatё O「 in ‐￨ ThrottbOё ytopenil Paientsl l ‐ I I .: T「 He16ま ど「 1 0=“ “し 1衝 '￨￨:lv″ 61革遇 T' 1=「 T]｀ ‐ ￨￨￨ ￨￨「 , PrOspective studles 、 : ‐ 二Op百 nt and Furooptttё tttalS(Ceru,) ￨ 二 II' 二 月OVOn 86(putchiBI。 Od Sё市ilё ) MI「 asOl tttal(Cattdian) 1 1 ￨ ‐ _‐ ￨■ お― 11111 0hterolo)† ￨latedPhb応 Contr01 plat,letξ P alhogeiredicOd SPRINT,tudy p 101ateゃ ￨。 PropOriOn ofptS With Crade 2 blё じding ‐ Days OfCradё 2 Ыё Odingl ‐ %patilitSWith Grad02‐ 4 b109dilg 111 , Surv9illance studieS On rOulne use Of PR platellts ‐ l l : ― France and Belgium 58.5% 57.5% 2.5 NS for infe"oHty 0.023 0.02 43 34 ‐ HOvON study Pathogen reduced platelets ， 一 %Ofpatients with l (〕 rade l-3 bllodittg Control platelets 19 p 0.034 り〇出 配布にっき、F D A の7 解済み。 1 布につき、F D A の了解済み。 配 11欅 1皐 :『 「 L堂1'111 と T帯 :馬 「 認樹ド 1:帯 ギ111■ 1,T需 clinical Trial PatientS in Study %9fplasmal P valte stored plateletS CCI atl hr SPRINT lta 645 ‐ 31% く0:001 HOVONl,b 184 ‐ 31% く010001 MIRASOL 2,c 118 -31% く0.0001 1「UVA/lsoralen 2=UVB/‖ bo“■n l ‐ 茎 辮 掛鵞 熙為秦r黎譜 竿￨ MIR、 ,OL Study Controlplatelets Pathogenl ieduoed p 01atelets %。 fpatientζ with Grad0 2-4 bleeding 30 NS : . 熙 FPA?了 布につき、 “済み。 配布につき、FDAの ア解済み」 AdverSёEvents Rё p6rted in the i ´.￨ ‐SPRINT Study can adverse evё nt signals calptured in a ёd and di cOntrO‖ pro,pective,randOrnittё nded Stuoy bO.eValuated ‖ 。 loh th「 a り 898 alverSe eャ e,t typeS Were reported bylbllnded obseⅣ ers ,passive adversereporting study? に :品E健:Y¶ 蹄 黒ぽ需機諾:話 器 1■￨ 40,the ll linicallシ wereこ siOhi轟 ht rlde ё 3 1nd 4 1 oら events: 1 =IHypocalcemia,syncOpe,Pneum601is,Acutё ‐ 尽eSpitttOry Distress Syndrome(ARDS) ‐ Snyder E et al.Transfusion,2005 Dec:45(12):1864‐ 75 Franceand Belgiumh,avebeenusingpathogenieduced plateletsfor severalyears Adverseeventson transfusedpatientsare reported througha passivehemovigilance reportingsystem Frequ-ency of reportingof adverseeventsis much lower thanwhatwas reportedin SPRINTtrial Thereis no activecontrolgroupto identifyevents speoifically relatedto PR platelets 卜〇［ ARDS Ratesiハ thё ttreatrnehiv.si tr8iTTicoλ ハrttS Ofthe sPRINT Studソ : ‐ der F et ranSfusion.2095 a!,丁 Snソ peci45(12):1864‐ 75 ' prospё etiヤ o・Ⅲ d blinded evaltati61sidurihO c‖ nicalthe tlia: : n t e r S1。 (PR) p10111ets Patients(N) !ё COntFOl platё ts 318 327 5 0 IARDS p value 0,03 Egggspgsgve review of medicalcharts by a blinded expert,panel interSOl(PR) p value contr。 ￨ platelets Patents(N) TOtal ACute Lung iniury (ALり 78 19(6.9%) Platelё ts 70 16(4,9%) 0:60 ARDS 12(3.8%) 5(1.10/ol 0.09 ALli non‐ ARDS 7(2.2%) 11(3.4%) Ot48 ￨ : 1 配 布につき、FDAの 了解済み。 こ 蹴肥 &槻:￨ 細:橘T創朧 「 馴‐ 108 彙= ・■4 ■ ■●■会 感染性因子低減化技術導入に係る費用対効果分析の報告(概要) 理由用資料 icorcmics of pathogen inaotivation bohnology for plitolet concantrator 論文タイトル Jamn of tho lhc oosfrffectivenoss of pat{rogon ]ost-effsativemss ヽ ssOssmont of tho ooooomiC Valu● of pathogen 'oduction tocfinology as ass6s6ed rehg a nactivatlon for gldolot tfansfu3ion in tho lN rERCEPT bl● ●d system in 3o!givm iletherlands nultigla risk ruduction mdol in Illt J Haelllat 2004,80:31732` 目 性因子低減化を想定し、決定木分析によりCEを評 価する。 熙感 染 症の リスクも含め 評 価 す る。 とにより感染性 因子低減 化処理を施した場合の全血襲 日(PRT WB)及 び血小板 製剤 (PRTや 0)の 費用対効果 ーニング法のCtと比較検討す る。 OE)を現在 のスグリ ∞st/LYG)で示し、直接及び固 権費用と便益を含む ベースライン分析及びモンテカル●シミュレーションを 用いた感度分析により評価 した。割31率は軍 %と し た。 ・放射線照射 ・ 細菌検査 (注:現状、未実施)等の中 ・ 低減化処理経 費を116ユー ロ、製造工程 中のPC損 失 止によるPR■ PC(15単 位)製造経費削減額10,908 分を1596と仮定する。この損失分を製造コストに上 乗ゼ 円に対しヽ低減化処理キ ット等の増額分が20806 し、低減化処理 費用を合算する。 正味の経費増 額になると ′ 円,差 引き1.898円/baφ ｀ グローニンゲン大学病院 における受血 者のPC輸 血豊 仮定。 ′ のフ割を占める3患 者群 (心臓 病 ・ 血液疾患 ・ 卜児がん) を薬剤 経済モデルとして選択した。 ・ 、 処理により 感染性 評 価モデルは 低減 1ヒ 因子が 10096低 減化されること、重篤な誦作用がないことを 前提とした。 けた乳がん患者 、冠動脈′ヽ イ′く ス術を受 けた患者群 を 評価対象とした。 ・ 3通 りのシナリオを設定し、導入効果をlCERにより評 価した。 シナリオ●検査内容 等は現状通り。アモトサレン法によ HOV HCV及 び細菌感業のリスクが排除 される。 りHⅣ ・ 新興感業症は考慮しない。 シナリオ21 0acT/Alertに よる細菌試験 を中止、PC有 効 で延長、期限切れ 率を1/2、成分採血ド 麟間を7 Flま ナーのALT検 査、成分採血PCの 放射線照射を中止。 シナリオ3:シナリオ2にカ ロえ、成分採血PCに ついて、 NAT(HCV・HⅣ)、梅毒検査を中止。 輸 血による新興感染症の感染リスクも考慮する。 ヽのCCを評価するo 分析対象として2007年を選 択、同年のデー タに基づき 乍業を行う。 検査方法 は現状通りとし、低減 化導入を想定 。 レシピエントは、全年齢群、低年齢群 (0-39歳)、高年 冷群 (40歳以上)の3群に分け.評 価を行う。 全年齢群を対象とする感度分析 (トルネードチャー ト、 取定した条件により、およそ70万本 のPRT‐PC製 て401ユーロとなつた。なお、「部のケースではv線 照 造に係る費用増額は、およそ273億 円となる。 ・アモトサレン法導入によるOALYに ついて各年齢 、 射費用30ユーロの節減が可能である。 ・ ベー スライン分析による各群の"t∞ st/LYGは、心臓 疾患別に算出した。ALLの 10歳児にPRT―PCを 輸血 ー ー ー した場合の99∞ 万円/QALYを ベースラインとしt更 病■74万ーユ ロ、血液疾患 678万ユ ロ 小児ガン 261万ユ ロであり、3群 の加 重平均値 は554万ユー ロ こ新興ウイル スに感染するケース(感染確率 (■6094万円)であった。 1/10000)を想定すると、35∞ 万円/OALYと なる。1 ・ ,アモトサレン法導入により費用対効果の改善が見 輸血用血液の安全性対策は、相対的に高額のnet cost/tYSで あり、国際的にも許容されている。今回の られ る。 分析結果も輸血医療においては許容範囲内と考えられ る。 : 感度分析から当該モデルは、回避されたウイルス感 染及び想定した固接費用の正確な金額を除外すること 轟 も滉 瞥翼 覺 諄 窮ぴ 輩 幡 警謝 淳 鞘『 ・ 感染リスクが1/10万回輸血になると、CEは 165万 -336万 ユーロ、1/10∞回輸血では223万 ユー ロ (■2450万 円)に改善される。感染リスクは1/1oo 回輸血では、全患者群においてアモトサレン導入 グル ニプのCEが 優位(少額)となった。 ・ ICCRは新興感染症の感染リスク、適応、患者年 齢にsensttvOで ある。 =現在法に対し、アモトサレン法導入グル ープが優 2・3で、各々 位となる輸血感染回数は、シナリオ1・ 1/1074・ 1/1697・ 1/1791回輸血であった。 ｀ である` ‐ 低減(ヒ推定処理 費用は 1∞ドル/回 。 PRT導 入により、感染リスクは、細菌て1,現状の 1/5011/235∼250万回輸 血)、H8Vよ 1/10(1/153万 faI輸 血)に減少すると推定され た。 PRT WB:こ おける`CERIよ、1276万 ドル/QALY(■ 102 億円 )となつた。この金額 は低年齢群では平 均より少な く、高年齢群では 多くなつた。 的 悪認議ち 雷猷撮鉤 会費用は含まない。 方 法 結 果 馴 麗L は 大 きい ことが 示 され た。 ま米国 では11万ドル (000万円 )/QALYて ある。これ に従 えば近年の輸血用血液の安全 対策 は何も実施 てきな ハ。低減 化技 術の導入に際しては、同領 域の施策と比 欧することが妥当である。これに1ま、30方ドル(■2400 万円 )/OALYの S/0血 漿.85Kl万ドル (■68億 円)/OAЦY つHCV NAT(フ ランス)が相 当する。 アモトサレン法導入 は、血 小板製剤の安全性 の改善に 苺与す ると もに、既存の製造 工程の簡略 化や新たな 隆査法の導入コスト等 が節減 可能になる。 Eン テカルロ分析) を 行う。 現 行の 堅 宋 た スクリー ニ ンク 蘇 査 員用 は4 4 トル/ トナ ー 9影 欝鑢称轟駐磯 ξ 糖齢猛需 幌 結 論 Transhslon 20 101∞ :2461247( 3( Transfusloll Medlcille 2006,16:17‐ Trallsfus10nヽおdlclne 2005;15:379‐ 33, .Cこ の評lal結 果か0ア モトサレン法の異馳は景当 医療の分野において国際的にも許容される範囲に である。将来の新興感染症発 生時の潜在的リスク あると考えられる。 し考慮するとき、同法はより有力な戦略といえる。 鸞 与 ζ9舞 ;I[彗 し【i]り 竹 譜``セi雪`:(I と、また、アモトサレンの安全性が実験的には確認 されたものの、アモトサレン法処理PCの 安全性 は 不確実なレベルにあることから、予期 しない副作用 により期待した便益が損なわれる可能性が否定で きない。 ￨ PRTや CにおIす るICFRは、1423万ドル/OALY(■114 平均獲得余剣 者て ￨ つた 事調鷲 智 γ尋 野 感度分析の結果、PRT=WBで は細薗感染が、PRI―PC では輸血による年間死亡者数が最も影響が大きい要素 であることが示された。 10ALY:成分採 血● bur“。atPO>成 分採血ゃlasrna iChPC)・ 本研究 結果から、患者の年齢及び身体の状況 がPRT 'C2Eに対して重要な決定 要因であることが示された。 PRTは 有害事 象のリスク減 少という点で不確実な点は 姜る。 . 輸 血R血 液の安全性向上 へ の取組み という点で、CE )析 を通してPRTに 係 る政策決定 の情 報を得 ることがで 雪る。 費用対効果分析。晨 なる臨床効果の冶療法を比較する場合に、発生する費用にアウトカム(QCL.余 命)を加えて評価する分析法 ICER Cncrement cost Erecbvenesso:増分 Ra● 費用(対)効果比) ￨ ER=椰 一 的に、この値が 二定の値より小ざす の増額分を右式により 小さければ導入は効率的と れば導入は効率的と評濡できる。 評価できる。 Ю 新規医療技術等 (B)の導入に際し、現在の技術(A)から 算出する。 額 分1右 により算出 o9T般 般的に、 'ω からの増 す ず :^[￨(覇 轟 馨 碧 照 違 霧 響 警 l鎮 幕について経済的評価を行う際 、健康上の利疑 数値化するために使用される方法。単に生存期間 の延 長を論じるのではなく、 生活の質 (00し)を表す効用値としてスコア化し、これに生存年数を掛け合わせt総 合的に評価する。ス コアは完全な健康を1、死亡を0とし、種々の健康状態をその間の値として計測する。 I Ex)10ALY=完 全な健康状態で生存する1年 円換算レニト11ドルー80円 、1ユ ーロ 110円とした。 また、カナダドル=OSド ルとした。 嘔崎鶏宣留:は鷺 い _年 、 1ま ξ現 :ょ お し ヒ 余 基 さ 薔 島 を 延長 る 0=必 要 を ぅ 。 =費 一 ３一０ヽ３“●Ｏ Ｄ”一ヽＯ Ｃヽうｏ一０︵ 謁 ¨ ， コ´ ‘′， コＣｃＦ ﹃工 一響 奨 〓 ｍｋ一 ＞日Ｏ ｒＯ Ｏ く 〓３く ■８８ュａｔ 智，￡９ ︻ ■８ ♂■８δ鍵 ぼ” 一 手 ｃ 一” ∽ テ 一 ■ ■ ２ ■ ■ ′ ， ﹀ ３ マ 一 こ 〓 ｃ ′三 ︶ ﹁¨ ” ヽ●一”ヨ ・ ，︹ｏ“ｏ一 〇 ０コのｏ■一一”一ｏ∽ 一 ・ こ Ｄ， ′ 亀 ■ ● Ａ ﹁ヽ８ 一一 σ ⊂ 〓 ∽Ｓ 咀 ●コ●゛ ヽ ｒ︹ 一 ｔ ３ っｏｃ Ｏｏ３ ∽コ コざ ７●３ ︺曽 忍 ｏ， ８ ンに“塁 ち ¨ 菅 一●●●一ｌ ε●ｃ一︰ ¨ 〓 ぢ ″ Ｂ ｃ２ ● ３ ３ 、 ま， Ｑ■ヽ 一ミ Ｑヽヽじ ミ¨ ・ 、 ヽｋｔ〓 ヽヽ ■ ■ ６ミニ ６ｏＳ ｔざヽ ミ 賓一ヽ ヽ■ミしヽ卜一 ′， Ｖヽ ， ´＾ Ｑ 〓ヽ本ヽ ・ ｃｃ４ ３ つ Ｏｃ ｔ′，１ 一 ｃα 二 〓 曇 ユ∽だ ｏ一 一﹁一¨ 一‘ゴ〓ニコ“ ﹃Ｃ， ︶ α・０＾ ” ｏＬ Ｃｒ〓一 Ｃ ，ｒメ︶ ご一 ヽＣａ 一 ︼ｏ﹂ ｃコ“Ｃヽ”一 コＯ ︶ ヽコｏ つｏこ´Ｃ¨Ｃ，´ く一一 ＯＣａ ¨，一ヨ′﹁Ｃ● Ｃコ 一 コ ﹂〓つ¨ ¨コ つｏ﹁‘′， ”ぅ一 ＞ 〓‘ ■●２ コ■ ︷¨一勢 託一 巽雷 請 中 野¨ 舞 瑳要﹂ 繁嘔 要¨ 計 慎 肇 一 難羅 一 機 鐸遷甕理機一 一 鶴 昨 攀 聖裁華凝一 諸華輯押 ． ﹂ 踪 一摯” ¨ 奨 、 こ ∽く‘ ｃヨ ︵一∞∽︶ご ﹁■ ， ２ ■ 一 そ ¨ ｃｃ一■ ■ ，ｃ´ ， マ 衿 お ●コ〓 “ コ だ 一Ｚ ﹁い 力 の ｍ ヽ ﹁ ” ● ´ 一コＣ， 一 つ ⊆ ， こ ´，﹁ あ 一ｏく２ ´ も ｏα ，二 う■２ ， 〓 ｃ こ ´つＣｃ■ ｃョ ｏ﹁ ﹁２ 〓つ“●コ′ ´ ● ＯＬ ヨ 〓 ， 一 〓 す﹁＾ ンヽ 夕 ｏ′ ０﹂ ， ａ ｃ， イ Ｃ ﹁０。ＣＯ一 ３ ０ ■′だ ｏ一 ■ し⊃４ Ｅ´‘ ■・■ ●３∽ヨ 一 ｏ一´ 一Ｄ 〓´デ ´一ＣａК て ● ¨ ¨ ■ ●´■ うち ﹁多 〓 ” ｒ ぢ ■ 号 〓 〓 彗 ■ ｉ こ ８ ， 〓 ヨ一 ＞３ ８ ３ ８ 〓 ３ ︻ 争 身 分 ヨ ＆ ε ′ ， ， ａ ａ 夕 ′ｏ七´ ７ ｊ Ｒ Ｆ ２ ３ ﹂ ■ ︶ ， 酪 菱 一 種舞 新 葺一 瑚 難一 一 窯咲 難 督 葬一 摯葉 なオ 一 一 一 一 経一 一 審 一 椰葦 撃数 一 一 一 轟 〓κ ﹁〓 ス 調 〓 夏 ｒ 一イ 一ヨ一ｃ﹁くＣ，一０コ′ ︵ ” ユＥＣ一 一 一● 一■Ｄ３，〓く す０〓 Ｃヽ 一，リ コ 一Ｊじ一 ・ 一 ｔｉ´Ｃ﹁ 丁ｒ︶ｏこ ´２一 一 一 ■一 Ｃ 一 ヨ ”ｏつＣ凛〓 ０一，こ﹁ ﹁ＯＣｏ，一 て ﹂Ｅ一 ´Ｃ¨ ●′〓 コ“︶ ，コα 一 ４ 鷲 年 ■ 一 一 ‘ ヶ 〓 Ｌ´ ， ， お ■ ， ａ ″ に ， ２ 〓 ２ こ ヨ Ｃ ２ ′ ｔ ８ 二 ヲ っ ′ ｒ ” く ■ ， ｏ だ ８ ヽ ｏ ” ， ｏ ′ ， ２ ， ブ ‘ お っ ｏ ｃ ， 一 〓，ｏヨ いも¨ ３ ● ｃ ， ´ ， ‘ く “ ¨ ﹁ １ 一． α ¨ 諄 ． ．。疑 三 嘔 コニ ． 、 ︶テ 湧 ︰ ×一一ｃ ¨ て 〓 一 ¨﹁﹁葬 ％軍 〓﹄″馨 罪 一一〓■ 一 “ 一 ¨ 一 ■ 勇 ｒ ヽヽ ミ ヽ ﹁ 〓〓 一 十 ∝０お ｔ ら 一一 一２ 二 ０ こ り︺ ご 工 ｃ一︵ ミ さ ヽ 収 ｘ︶ 弱 歪 藤 ﹂ 市電 在 一〓一 アドヨ〆 ど電ｏｃ 〇０ ︵ 一¨ ｃｔ ａ 一ｃコ 一 ０疑 ・ ｃ一 ・ Ｉ 蒻 ヽ Ｃ一マ σＣ¨ 一Ｃコ 一 ＾ ´α 一一 ´ 一 一″´ ”う﹂ ｃＣ‘ ∽ ‘ ＪＯ● 一５ ■ ｏＣ Ｃュ ●” ■一‘ ，一 ＾︶ 一´ 一Ｃ︸ ０“一 一〇Ｃ，Ｄｏ 一 “〓一コＣ”ａコ 一 Ｅ■●〓 く一〓Ｃ■ 一ＣＣｒ〓３Ｆ︶“一 α′ ´ＥＣＦ “´ 一すｏ 一Ｚ ﹁ ［ ” つ ” ”﹁ ∞ 一 ＾ ν＾ ︶α ∽︼４ ■ヨ ︵一” ∽︶ Ｐヽ ﹁Ｆ 澪 汀 ， Ｐ ´′ ﹃ｃＬ ， 澪 ヽｃａ モ 〓〓 一すｏ ｍ ﹂﹁●一ｎ，３ ０ ０，３ ﹁８ 〓Ｇ 口 ″ 一 ヽｃｏ一●● ︵の 口 ︶ Ｌ σ一 プ ０ 一すＯ ＣＯｒ ＾ ｏＣＣ コ一ｏ﹁ｒ・ｏ﹁ｏ ｃス﹁●Ｃ︵Ｃα ¨Ｃ 、こ■ すｏ﹁ 一 コｏ﹁●︹ ５〇 三︵ ン 一ぉ 〓ｏ■ ァ、 ●コｏチ ヽ ︶ ０こ ｏｏ３ つＯＤＯコ， づ 喘 ぉ ヽ ｏ■ ¨ゴ● ｏ︵ 、●ヽ 一ゴ一 ′ 一ゝつｏ Ｃ一 一 コ´０ヽ‘●コ一０， 一 一＾ ︶﹁ ０●コｒＣ，コ 一 Ｃ Ｊｃ，〓す ０●〓ｏ︶ 井 ｑ ′一 ２ ＞ ¨５ ｏ ‘ ヨ ｏ ■３ ， つ２ ，０”ｃつ す ●２ 〓 〓 ３ っ ８ ｏ７ ヨ＾ ■ つ﹁＾ ■■“ ﹀ 一 ● ｏｏヨ ﹁澪 ゴ０コュ ‘色 て 一 Ｙ Ｑ ヴご ●一 ´ ＣＸつＣａ〓 ﹂ 一 ＾ ｏ 〓 ■ 一ミヽ ´ ﹂ や〓 一 ソ Ｆ の ｃ´一 ● ﹁お ， ■ 口 だ ″′ ´に Ｃコ す ｏ２ ● 〓 ， Ｐ ﹂一つ■， ｍｏ●コｏ， お ′ の ＾ ︼¨妻 一・︼つ一■ ︶Ｌ●一〓 ●● 萎 コゴ ｃ 一﹂一 ヱ 一 コα σ一 〇Ｏα ´Ｃｏつ一ヽ一 ●， ︵ う ﹂，ｏＯコ す”∽ Ｏｏす一 Ｃくｏ﹂ ｏ ヽ 勇 ，一 すｏ ‘一 ０‘ユ一 一ｃ゛ｏ﹁ ｏ，α 一 コイ＾ ︶ つ ｏ一 ´ｏつ４二‘● 林 ︶ “す ごく●一，コｏ● ´ こ ‘〓 ヽ 一 ∽ ｃ● ｃうす“ ●∽夕 一 こ 〓∝■ｏてｏＦ る 一 一バ● ｏ﹁■●コｏど Ｌ︵ う・ Ｏｏ´， ８ 一 すｏ ｃ一 ■●コ′ヨ 〓おｃ ， Ｐ，一 ０●〓 コ 、 一 〇 ０︹〓“〓 ﹀ ｏ３０﹁ 輩 一 く 工 ０く 工 ∞ く ヽつと すＥ“ ︵工 一 ８ コ ﹁ そ， ■６ 一 ３ ■ｏ 馳髪 メ 鍔 勇 “三 一 姜 誠一 葬 調 革． ¨一 奨 ﹃ 舞 猛 一 一 一 一 ¨ 一 嗜 稀 課 髪 ﹁ 艶 車 調嚢ゴ ﹁翌 ¨ ． 誇コ ． 一 一 礎謁経罐﹄﹁ 葬菱理 一 ¨ ］ 一 誘 “鵞ず一 ¨ ︼贄〓二 一 ご ”こヲ つ０一 言勇 棄 一 ≠ｏ 馨錯 メ 華 ︰ ︰ ¨ ︵一 コつＣ´ ”﹁Ｃ¨ ゴっ﹁ Ｃヽ﹁‘´つ３つ﹂にっＣα ｏ，ａ ﹁●つュ ニ＾﹃●￡ｇｃ´´４ ″〓一∽Ｆ一 “一 ン′＾ 〓 オ ン く０ 一一“エ ン ， ´ く︻ ＾ 〓 一″ Ｃ 一ン ¨ ´ と ， Ｆ イ 一一﹁一 く＾ ﹁● ′ イ 一 一ぉ ■ ， ■ ■＾ ｔ´ 一 一 ニケ ´ ︼一 ９ ヨ¨ ¨´ ´ し午´ コ，， ●■ 一ヨ ー ３′２ 一●ヨ ︶ 109 _J Ｐに ビにに〓 ドにけにいにはドヽ ヨ ，望 ● 〓 一 Ｔ一 ■ ｏヽ≦ こ一ヽｏα ”ヽ，ＲＬ ︵ｏユ ヽヨヨヽ こう ｑ ωＯｏ０ ヨヽ●α ”０ ミｔＬ ”一 ¨ 請け ヨ ︺ミ ︺ ミ 妻 萎一 沖湊 一 ごミ ≧ て 一 ∝， い０３一 ュ´ｏＤ・ｏ た０，口 ０ 會Ｏｏ ● つ ■ 〓″うこｏ Ｊ 一 刃 ， ●ヽ﹁ ε ， Ｏ” ０ 一〇Ｏ Ｄ ” ０ ３． ω ﹁ 、ヽ ヽミ ヽ ェｃ３ ●Ｄ ¨ ｔ一 ヨ ョ ｃＲ こ ０ま＾一 ｏ一２ く一 ﹁ ５ 一ヽ ふひ∞ ０００ ■ 一 一 ェｏＯ●¨ ¨ 〓 ∝ く一 一ヽ９■０∞∞ ■ 一Ｎ︼ ﹃ Ｃ´ 〓≒ ︵メ テ ィ 一二 Ｐ へ雪 ヽ く３ ８ ご ８ ８ ぎ ヽ ヽＭ ８ Ｖ Ｅ 一 ． 一 ＞”鸞 ，ｏ，一 こ●４，∞ ８ｏ﹂，ｄコ０ヽコｃ︵ ｏ＾ヽ わ “ 燿 距 ・ ¨ 一巧 静 ﹁ 電 一 ﹁ ¨一 話 一一議 馨 一 ´ 三 ， 一出 Ｚ ｏ α〓 一 ・・ ゲつ０お ﹁一 ′ ら一 Ｃ一二 Ｑ ユ ８ 手 ３ ３ ， ， ‘■ ， ３ 一 Ｓ Ｉ 一三 ｇ Ｃ ケ３ ＾一 濯 ８７ こ ｃ●ヨ 一〓 ゴ●コ´ 一 くＣ う０ヨ ご，ヨ ， ´，ｃ一く〓一 Ｃ〓 ００ す ●，９ ■ ２一，一 ， ｒ こ σ一コＣＰ ′ｏ一多 ア ● ｏ ご σ“マ ヨ¨ ５ コ０﹁ ョ て三 ０ ２一●●′′ ，一 こ α ， ご 一 〓 ｒ す Ｌ ，﹃ｏ ，こ ′ ι月 ｃ ヽ Ｅ 一 ご ｃ一●ｎＣ，︶ ３″ ｃ ，ｇ ｃ ′２′ 〓 ´ ´ ■●つ●２ ｃ¨ ５ ，ｃ⊆〓 でコ ヨゲ ，０﹂﹁ 〓一 ●チ 〓だ ′ ｏ，‘ ´こｃヽ ●コ′そｏ¨ ３● Ｏｏ■ ，３ ヨ 望 ， ， ｏ﹁ 一 αＥｃ〓ｏ３ ０﹁一 ｃｃ′ｒｃ〓ｒｃ〓‘●コ●′′０一¨す一 〓〓 Ｆ︶ ，Ｃ 一∞ ∽ 一 ３ ﹂●つＳ， ●●α ■言 っ′７● 〓澪〓Ｅ お ●ｏＬザ ′ ‘ 〓ｏす ｏ﹁ζ ｏ■ ，α ＞ ｃｇゴつ一 一 ■ｃく ヽコ﹂ ﹁Ｃごζ●Ｌ ′ヽ′ｃｏｏ﹂〓０一 ＣＣ 一 ｏ﹁︶ ■ゴヽ三●コ 一 一 ●●Ｃヽ ， ｏ﹁ Ｃ一 ，一 プ４●●α〓ｏ，ンすＦメ︶ Ｌ一 ﹃ ●，一０●´ ，，７●Ｃ´‘■，一一 ヽ ，コ′ ﹃一 ■¨ ●■Ｃ４う，多′ 〓‘ ｏｃ， Ｆ ａ ｃｃ二 ′ ｃ ﹂ ， ■ ■ ３ 〓 Ｌ Ｏ， ， ■ ■ ■ ， ｃ′ 〓´ ﹂３一●３ ” ＯＬ ︵“■ ︶゛′ 一〓︶ ｏＬ ７，コォ一 コい つ﹁つｏ﹂ａ Ｃ﹁■′ 一 ′ ´ ︶２ ・ ¨ヨα ´，０■ ¨ ． 一‘ ■ 一一 こつ 〓 ｏ●′¨′ 一 Ｃ Ｃ´ ‘”´Ｃ 一，Ｃ 一コン﹁¨ る ´●二 ” ∽ つ〓一¨ｏ一 ｃ¨∽ ● コ ″一 ¨ ●一 ． ， Ｆメ一● ● ●● 本一つ” ・ つ 一 ｒＣ Ｃコし一 Ｃ ＣＳ一 ＯＣ一 ，一 ■ 一，Ｃ Ｃｏ′一 ＣＣ ，′こ・ ス●一 Ｏ ＣＣ，●●′ → ´Ｃ一 ｏＯ●こ ヽヨα ｏ０４ ・０﹁お ， Ｉ ｏ●●′∽ ● ︵ 一すｏ 一” ∽ ３ つご ｆ ″ 一，α３ ‘ ヨ ｃご α〓 “ 屁 ﹁Ｆ ｃｃョ ｃョ 。﹁一●ＤＯ﹁ ■ 一 ′ ヨ ２ ■一 二 “〓 ョョ 〓 キＥ 〓 〓 す 〓 ，く つ８ ・ ７ ｏ ∽２ ■ ● ユ 澪 ■ ・ ´ ● ●ョ ｃｔ ＾ ‘Ｃつ二Ｃ３ つ﹁一 ●′′︶ ｃ〓二０こ “，■■‘ｏ﹁ ′ｃ′Ｌ´Ｃ′一一丼●●´ｃ ‘Ｌケヨ， ﹁０一′﹁ 一 ０● コ一０ ● 一 ● 一 ０ ● ０一Ｃ ■ 一 ， ● ′゛Ё ︶． 二 ａ Ｃ ´ａ ｒ ｔ ´´● コ ´ ′ 一 コ ﹂ ﹁３ つ ご Ｃ″ 一 ﹁ｏ ﹁ 一 ｔ ， ヨ ー ｃ′ ，■ ３ ， ● つヽ ど ご ﹁‘ К お ｃコ， ” 一 ，一 ′ ͡Ｆ 〓 ● 一︶ ［４ 一 Ｈ●デお ”・ 一 ゞ ぎ ︱ ﹁ Ｒ ｏ３ ヽ ｏ 忍 ●´９ 一 “ ”ａ よ ´ｃョ ■ ９ ．●一 ９ 〓 ス ， ３ ¨”ヨ ∋ ● ■ ，α一 ０ ●ヨ ヨ ” ■ ，ａ一 営 ０ コ ＞一 ％ ０一 ３ ９ ¨Ｌ Ｏ一 ， い ヽ ｏ ¨お 髯 Ｏα ‘ 一 ●ｇＯう δ ユ Ｊ● ヌ ２ つ２ 一 ｏＤ Ｒ Ｆ ｉ ， ０８ ． す ■ｏ ，Ｓ摯●コδヽ オ〓ｅ ﹁ ，く 一 ，ままｏ ０３い■よｏ ●３Ｑ ， ヨヨ”一 ”澪Ｆを” 一 ３●︵‘く〓 δ う Ｒ ＨＡ ●一 い０ ２ 一 ３ ■●ョ ０ュ 算 ● コ ， 手 ｏ ３ 一■ ｏＯこ お ■Ｒ ” ∝ｏヨ ３ ● 一 一 ﹁ ヽ ”０，一 ０， ＆ ‘ ３ ， ■ ３ ‘ε こ ７ ８ 一 ｒ ´ ＆ 〓 ， ６ ●３ つ と ， 〓 ６ ≡ 一 ■ ヽ ３ ３ 一Ｆ 〓 ″ ６三 一 ０“一 Ｊ ´１８ 一 ´ Ｏ Ｌ Ｏ■ いセ 一 Ｒ ６ ６ Ｎ８ ヨ ｒ ｔ ＯＦ ３ ● Ｂ Ｇ 三 ●ェ 〓 ぉ 害 ０ 一２ ＆ す０い０３ ，●， ｔ〓ざ ， ｏｏ一 一●一 ″︵ お ゛ 一２一０﹁ 一 一Ｃ り、Юぃ つ０〓 ２ 一 ﹂ＯＤ﹂ ，●６ 一 ２ 一２ 一 ”一５０α一 ｏ●０３一■ ０ぷ ︶． 一一し 二 ・ ・ｏ ，ｏ∞︶ ＮＯ ∞０い ゛Ｃσ＾ ︵ 〇一 ﹄一 一 ・ ＺＯ一 ， ●゛ ω∞０∞ ´ ＾０■ ■す０つ ●０，一つい ヽ０一●８４●■●″●● ｔ一 ｏ， 一′ ■ ●え ０２ つ一 Ｒ Ｏ ヽ３ ヨ ヨ フ ヨ ´■■ う ． ョｏ ３４８ｔ“ ︵ ” ． 一 Ｉ． ■ま¨ 尋■曾。 豪聾討． 要σ 一 醤訂Ｉ。 ［ Ｊ ｉｍ ． 晴 ｃ δ 。 ． ｌ． ﹁ 霊 講一 ¨ 繁¨ ﹂ 萎詳﹃ 墨誕﹁ 襲¨ 難一 一 ぶ。 震要・ ﹁ ´営 ●〓， ζ Ｏ 電 ヽ 一 Ｆ ｏつ つＲ い０コＬ ｏｏヨ ヨ ｃＤ一 ＯＰ ど ぞ 時父 ヽ ８ ¨ ，゛０” 十一”い ，ｏつュ● ＯαＯ，″ ●０、一公︶ョｒｏヽヽ おい ヨ” ｏ●■●一 ”ｍ■一 ヨ摯●σ”い ｏつｏ●ぅ０２● ０こ０３ｍＣヽ κ ”ω６︺“ 一い０一 の ＞ ∞Ｏ γ●●一 つ〓 〓 ユ ＾‘ョａｃ晨 ， コ嘔 一３“ ︵ 一 〓 寝 〓 〓 ● アくつｏ‘ “Ｅ 一 静 み 〓す ”﹁ ョ 毛 ダ ｔ てｏ﹁ ︰ ３ 一３ ８ ｇ ■ マ ｏ，３ 三 〓 ュ マ ¨ Ｉ ｃ‘ ３ 争 ３ ∽ の´ てぎ ｏ３ ヨ ｇ ， お ｉ ｆ つ〓 〓 二 ﹃３ 一ダ 一 一 ０５８■，ｃ イ，も・ 一 ¨ 一 ユニ ，そｑＣ‘″０ ● ８つ し ｏ っ 〓” ド一■け澪コ ﹀ ＬＱ“一 ３”■一 ，■︵ 〓〓●一 ︶ 〓きョ´‘ ８ａ ■■こ〓〓 コ ｃ メ●ｒ二﹁ ﹁ 卜 留 ，ュ ， ７ ● 、 ≧ ミ ・らヽ ﹄ ´ ︵ ｏケ■の ヽ も κミ ヽ ヽ 、 ＾、¨ ミヽ と ヽヽ ヽ ミ ■ ●´ をヽミ ヽ 冴 ︶ 一 ヽ へ ﹃ プａ ｃ， ｔ Ｃュ 一 一 二 一 〓ｃａｃユコ“ ● コ●‘ 一 ０”︶ ヨ つ，， ´ 一 一 ａ２一っっ一 υＣ Ｏ ′ つ ﹁Ｃ玄′Ｃ ｔ 一● 一 Ｌ一 ・一 ， 一 Ｃ α ００ ′ｒ ｎＣ コ ′ｃ ｒ ｃ ｃ コ 。 ● ¨ ｏ■ ， 一 一３ ● 一 マ ´″ ゴ “″ “つ●一 ｃＰ ′ 多 ｃ ， 〓 ２ ，壼 ｔｒ コぢ 一 ａヨ ｃ二 〓 “ 多 ｃ ‘ ， ，ｃ一 す写 ・つ。 て０〓 夕 一０お ユ 一 Ｌ ａｃて・ ョ し ヽ′ ´ Ｆｃ一 ︶ ´ ヌ︶ 一 ‘ お ●ヨ タツ、 ｃ■ 孫 馨 髪 ¨¨一¨絆 聟 調 耀 〓 ゴ 碑 勇 〓 ■ 辞 一 ¨ ■︶ 〓 ● ５ “夕 К ，イ ユ● ●●二 ３ つ３ 一２ 〓 ョ ８２ ｃ一 ´ Ｐ 多 ｑ ｏす︼ ヽ 〓一 ヨ●■ ｏ一一コ●三 手 〓ｏすヨ姜Ｆマヨ 澪２ ｏュ ●・ て■６ 三 うＯｃ， ′，■ ﹀ ｒ 〓 ”〓一ｃ。な ｏコ﹂０〓８一ヨｃｃ〓 ｏ■︶ ご′ョ一 ご 一 ｏ，ヨ一 ヽ ｃ 〓■つ﹂ｃ Ｅ 一 駐 ，ＣＣ ︻ つ ヽｏＣ∽， Ｃ〓 ＣＣ〓 くｏコｃ‘， ゛●０す ●゛ ｃｏ∽一つ↑﹃ 〓一Ｃ，７０じ﹁︵ｒマ ︶ “，一 レ﹁ 〓 イ ●３ 易 ぉ ﹂ 三 ■ ︶ 、 ０３ 一つｑ Ｏ， ´ ｃｔ ︵Ｏ ＞ 戸ｋ ︶“●す ｏ﹂ ヲ ‘‘ ﹂ デ 〓 一ｔ ，３ 一 一 ´３ ｃ一 ■ ち 〓 ，Ｚ ・ 〓、 じ ‘ ０﹂ｃＲ ｃ ４﹁ ′″ ョ つ ，こ ら ＾ 一 ８一 一 ，ｃ ﹃ｃ一 Ｃｔ一■〓ｏこ ”３﹂ ＣＣ‘ ●く，コ，つｏ﹁ ´一 ＾ 〓イ¨ Ｓ一 ●Ｃ一 Ｃ一 ，Ｃ路 一一 一 ︶‘´ 一 一 くつご ， 夕 ´一 ＯＩ ｏ■ 一 コ“ 一 イ “，Ｃａ ヨ 〓 ０９ 一●●一者 ‘‘ｏうｏｃｒ 、 ョ ヽ 一 一”∽ す ｏ ´‘ Ｅ ヨ 〓 ぉ Ｆ〓 ご コ 〓 ﹄”﹁”， イ禽 ０ ９ ´ 〓‘ Ｆ α ´ ち ｉｃ ，一 ′一 ′ Ｃヽ９く，〓〓ケ一 ﹁Ｃコ一つＣ●〓′，Ｇα ﹂つ０ つて¨′●コ″一 一 ら一 つ手し，ユ●■●つ 一 ｏｏ´︵ Ｃ●一´■一Ｌっ一 ０，二●● 一ｏ﹂﹁ 一，す一 ｏ い︶¨ ¨ヽ いヽ ，・ やヽ ヽ ・ ヽ ′ 一 こ澪 ︵ Ｑ¨ ＾ Ｅ一ヽヽ ■，●■ ミミ 警 続 ¨ 鋼 郷 蹴 一中 一 簿 癬 轟 一 諄 一 赫 ︼ ﹄ 〓 一 彙 一一 一 輝 ¨ 粋 一準 ♯ 螂 一 一 ・ ． 勇¨ ７・ 設麗ゼ 純梁霧雰亀 亀一 ﹁ 髯輩 ¨ ″ 一稗 一 髪 努押 委︼ 鍔¨ 積 一 零蝶 一 話¨ ” 裏 一 揚一 零 一 一 ﹁ ０そ ０﹁ 一７一 ｏＯ， ，Ｃ〓 ０一¨一 ●●， 一コｏＣ ■ ｎα コゴ 乖 一 “０っ０∽゛ ﹁“， ０ ͡●” ¨ゴａ ¨ 戸ソく０﹁ ¨〓● ●●多” ３〇一 ︶・一一ｏ σＣ一´Ｃ一 一 ∽ 一すｏ ｏＣ﹁ Ｃ，〓 ０﹁ ゴ●・〓 ７一“一一 一 一 す０ 一 くＬ ｃｃ Ｃ﹁一 ｐａ ヽ くＣコ一 ｏＰ Ｏ一‘て ｏ〓ｃＯ一 くｏコｃ一●●コ，一 ×４一ア ●′ｏこ ¨ Ｏ Ｌ す ‘ ０●ヨ ﹁お ゴ一３´一 くｏ ●●ヨ つ●一 お ﹁コ，ュてｏ 一 ∽●コ多 す■ でｃｃ３ ，一 Ｉ ｃＳ ｏＬ 一 ｃｃｒ■ 手 梃 〓゛ → ” Ｚ＞﹁ くｏ， ｃ一 一〓 すｏ“ｏ● ヨ ヽ■ ぞ 常 お ， ぞ ●コ●′ ”ヨα Ｏつ′ ・ ２´ 一 ■ 〓 ¨ご うγ ｃｃヨ げ， 〓 “ 生す 〓Ｌ ｏ︹ ７■ ０，コ●●´ σＯ ｏ，マ すＣ一■ヽ す コド一 〓 ﹁ 一 ︶ ０ ，ＯＣ ，ａＳ ¨ ｏヽヨ 〓 ざ ， 一 ﹁ ４ ¨ ， Ｃ●゛´ ， ０●Ｄ゛０工‘●●０， ，コ”一′一 ｏ﹁ ｏＬ 一 ′ 一ヽ 一 一コ ´‘ゴ 一 Ｃ ゴ 一， Ｃ 一ヨ ｏ﹁０ ・ 手 多 ０ ●κ ｔ ＞一 〓 ８ ４ ａ Ｏご ａ ｏ ＞ ｒメｒ 多 ３ 〓 ａ ｔ一 ヨ‘ 一 〓′ ，ｃαｔ ４３ 〓 ● ■ｃ 多 ｆ Ｏ●′す お 〓ヽ て夕 ０マュＣ〓Ｏα ∽一 ヨ一 ｆ 一 ■一 びマ 〓 す● ｃｏく０２′，コ﹂ Ｏｃ８ｏ３ ｃ一３ ３ ●ｏ〓 〓ユ 一。﹁， 〓′ご ′ Ｆ一 一 こ ３一 ８ ﹁ ョ ９ 一 つ一 〓´ ■一 ■ ，檜 〓 ﹂”一３ 一ｔ ｒ ｃコ´ 手 〓 ｏ８ ´ つ２●ユ ´ｃコａｃ〓 ２ コ“ゴ一●〓 ＾ ●マ ︶ ＾ も， ■ お つ﹁ “●ユ ５ ﹁８ 〓■，コ′一一 野 ¨ 議 菱 電 奮聖 勇 疇一 ¨ 詳 誕 ′ｃｏ■ 一 ●α ，マ 手 ・ 一 ご ゛‘ コ あわヽ ″ ，ォ０●， ′ ■字 ， お ｏ●●コ一 ｏｏ二 お Ｆ ﹁ お﹁ ﹀ヽ ヨＬ ●●レ一 二 ０一一．一 ヽ ・ ０ヨｏ ヽ夕¨ ヽへ ヽ一一ヽ■，じ‘ 総α脱 ゛３，■ｏヽ 一うｏ一 ．ζ 含 い︺ じ ︲ 一 ■ ■ ″ ヨ 一●■，コ・ヽコば ・ヽ ・ ● 一７ 一〓﹁ｏ Ｏ﹁つ０●ユ ●●一 ヨ お く〓 ｃ● オ 一 ヽＯＦ ＤｇＬ 一δｏ０ ０●Ｄκ； ” ｍす ０一 す０ ５ ８ ＾ ｏ又 口すｏＱ ゛ゝ 澪 ヨ 一∞´ ゴ と ０一コ ， ＞αｏ， ０つ ｑ ” ｏい〓 一 ０，０一 ｃ〓 ２ ２●こ ２ ＆ 争 〓 ＞く，３ ヨ■ ヽ どこお ヽ ，８，ヽ Ｒ● うい一 ＞ αＯＦ一 ０コＬ ００， ・ ﹄●■ 一 Ｄ ″ ｃｃ ︹ ﹃●夕′ 一 ン一 Ｐ年峯 巽一 一 ¨ 議一 臨弱巨 ﹁鷲 電´ 翌夢 ¨ ´一 一 ３〓 こ，，口毛ｔａｔ ■ヨヨ一 ヨ 澪一 イ ０ ‘ ご一 ピ一 ε手´ も考ｒ︶ ｃ 一 矩一 潤■ ・ 聾菱墨翼． 一 ﹂ 一 孵塁¨ 一 一 ﹁ 解年 撃喘 デ神 ・ こ 多 一‘ コ ｉ ｒ ｃｃ４ 一 ｇ ＯＬ ﹁ｃ て 一 ラ ０●多Ｆ ¨ ¨ ＾ イ ａ し ， も ご ■■ ３ ● ｏ‘■ ｃュ ↑ 一 σК ∞ 一〓 Ｃ一〓二 ，コ ，一 К 二 ０ コ´。 こ 一Ｌ Ｃ く０ Ｃ ｏ ■ 一 ︵ ωωＯ︺︶ ＾ コイ ﹂●ｏヽつ ”ｃｃ Ｏ﹁ ︶ 当 ｃう， ョ ′ ｏ２ ″， ゛ Ｌ 一一Ｆ ａ Ｆ 一ｏｏ３ ﹁´ ０つｏっ、 ﹂ ﹁一●つしヽＣα ，， ﹂ヽつ●一 一 す↑ ”﹁０，´ こ●■一 ´一 ，”一 Ｃ， 一 ３＾ て ＯＣｒ一 び ， 一 こ ﹂ ，´ ， ´ １ ９ ， ■ ・″ 一 ９ｏ一 ・， ︵＞ コ 〓 上 ュ ﹁＾ ｃ２ つ ｏ ﹁〓 ｏ﹂０コ 一 α３ 一 ご つＬ ， ｃ● ご， ３ ●﹀ 丁ワ● ５ ，ｃｃ２ 一 ８一 ●２ ５ 一 ﹁８ ｃ， ｒ ‘ 一 〓 母 〓 ‘ツ ，︶ ■ｏ， ， 千 ワ■‘ 一 に， ヽ ■ ゃヽ ３ ア な′ Ｊ ´ ☆︶ ョヽ 一 “・フ員●一 一 〓●ヽ， ●■ ●一 りヽヨ軋 ヤ“ ●ヽ ︵ ０００ ︶ ３ ■ ０ 一●︶ ．↓ｏ 一 すｏ すｏいう ０ヽ ¨ 一〇〇 ０●ヽ ＾Ｏヽ″ ；Ｏ Ｏ、く﹁一︺・ ぅｏコ＾，い●αα一 ０コ０一ｏ〇一 つ ０●、 ” Ｘ 一０二 。一 ●一 ｏ″＾ 一 ・ ヽ ′Ｖ一て ■ ３ ■ ■汚 ●一 ＾ｃ 〓¨ ●ｎｃｃａ ｍ‘に ヽお ¨ 一■ ´〓 〓 ３ ｃ Ｐ ＾ ■ ｃ″ ｃｃ一３” 一すｏ 〓” 一′一〓 一 ¨ ´ ¨ ´ ● 生 ′一 ラ二 一〓︶′夕 ●﹁つＦ 一 ｃ 一”∽ ¨ マ﹃ ３ 一一 ヨ ﹁Ｔ 〓 ●´ σヽ′０こ Ｌ¨●‘ｏ●﹂ コし， 一 ︶ ＞ 〓簿 ﹁ ●一 ●ＯＬ モ”ｔａｎてユ ︹ ｇ＾ ・ ０■Ｑ ァ●Ｏｏ●コｏ日 〓 ｏ＾ ‘′●コ０ ２ ， お〓 ●Ｃ¨ ●ｏヨ ｃ∽ｓ゛贄Ｘ ご ″ ０ 一 ︶ ｃ 奮ι ｏι ¨ ●一 プＣ 一口∽ δ 一 多 一 争 二κ Ｃ浄 ｏ﹁ ´一 ｇ ？ ン ” ■８ ８ α 姜 一 コに一 ， こ＾ ＞ ”二 ∞∽γョ 〓 ３コ一一 一す マ ■ 〓 色 贅 ´︵ ヽ゛デ そ 計 ７●４ α ｏ， ， ｃ ａ０〇一 く ・ いヽ や ﹀ ミミヽ ， ヽ ヽ ” ざ ミ 、 ヽヽ ミ ミ ミ ヽ︵だ︶ ●， ■ ミ む ヽ ■ Ｓ べ ヽ 奏 ︱ や ヽいい ０ ヽヽミミヽ ヾ● て ヽヽ ヽ ヽ ヽ ■ ′︹ Ｆ ﹁´ ， ア ‘ コイ α ‘ ，ｃ ，つマ ●４ ヨ ■ ■ て く０●け ゴ ´オ ツ 争 〓 ３ ● ′ｔ ａ ■ ︵Ｆ ´ ｒ ′一´ ■ ■ｔ ａ 〓 ｔ ａ一 ヨ 〓 ｃ ｉ ｎど ｃｃｃ ｉ ｃ ，︶ ′， δ ﹁ヨ 〓 ｃ■ 二 〓こ つら， ■ ■ ２ Ｆ︶ ‘ 〓 ， ア ´ ′２ ｒ ， ， ■ ，フ フ︶ コ● 一∞∽ オヽ ﹁一 一 ●´ つ´ ●一 Ｃ， 一 つ ﹄，つ，コ ●プ４ ０７﹂ ， ＣＯ■くｏ′ ｏ﹁〓二′ ´一 そ ↑〓 Ｄ〓 こ こ ，´ ｏ﹁＾ ● こ ヨ “ ョ Ｆ ﹁ヨ ョ び ３ つっ ， Ｃ ●■ ｏ︵ ︶ ‘ “一 “α ００， ＞くｇ Ｑ″Ｄｏｏ ｑ ””ヨ ヨ ， 一 ■”０﹂ δ コ ＯＩ ３ ● ｒ ｉ 翻 〓 ０ ６ ， ぬュ ａ 〓 嬌 ６ 三 ｇ 聾 α ︵ ＞くＯ ″，︵ｏｏ σ一■●ユ ¨ 一，ヨ“ ｃュ ａ ，＾ 〓 ∽ ”∽ ３一 一 一 一 ァ． ゴ 一 すｏ 一 ″■ ´ 一 ´ｃ ｃＯつ´ 〓´ ＾ こ′ ２ ， ， ‘一 Ｅ´ ●﹁ ィｏ﹁ ● 一 一 ．′ す・ ´ ・パ´ ｃ′ ． 生 。コｃ一 ¨一 ．ラ Ｃκっ。一 っ ． ． ﹁ ¨ 一ｔ 一 ﹂ ﹂〓一 ¨一﹁一一 “ ¨一 一 一 ︶ Ｊ だ ８ ‘ ヱ 多 ｃ あ ∽ ３ １ １ ，１ ，ア ニ 〓 ｖ 一〓 一 ■ ，， ■ ５ Ｌ﹁ ●３ｏ Ｎ ｃ ニコヽｏ ■α●一 ∽ ′、 ﹁ ｏコ ´ア＾ つ‘・ ０ ０コ′ ｃｒｃｃ，ｃ ａ， ´ ′，Ｃ〓 一●二´ 一 一 ９´ ■ つた〓︶ 一 ´ ¨ 一 ５一０﹁くご‘ ´ ´ ｃｃ ０ ●ヨお′＾ ら二‘一 ＾ コイ〓７ ■´〓¨ つ´ “ ００■ 一留 “３２■ Ｇ ”一 ”ヽヽ ミヽ ヽヽ Ｑミーヽ ■ ・ ﹁ ﹁●０一 ● “・ ︵９ ¨∩９ ８〓 ３ ０ ●ｆ ａ ，こョ〓 ９ ｑ ，●ｚ， ０９■ ｏ■ ｇ ，︱ ︵ ３一 一 ３ 〓ｏヽＢ カ 鸞ｏｏα ∽ヽおョ ︵ 一゛ 一 ● Ｄ“一 ０コ一 ● く一 つ０一 尋 す● ，コ，一 ｏ ﹂つ¨ ，一 ｏ﹁，多‘ ， や ｏ﹁“一 つｏ﹁つｏ′Ｃ Ｃ一一 マ４ ，そ ■ Ｃ″ｃａ ●く，一，ケ一 一， ＤＯｒ ５ ０ Ｃ ∽ ， ｃＳ ｃ● Ｔ ２ ， 翼中 ■ヽ夢輩﹃ 締神姿一 社 鍵議一 一 一 発ぶ 一 調 訴一 薇 ヨ α¨ け 一 イ ユ 一 ，′ 一一 ‘ 〓て 逮 〓 ２■ イ Ｅ 〓 マ や●■ つ一 ■ ■ ■ ■ ｏ９ ´ ´０９ イ ●み 一●こ ”′ 。。ご お ０ ヨ ＾ ゴα 〓一ｏ﹁●一Ｃ﹁， コ﹁お 一ｏ﹃ ｏ﹁● ″ヽ ´７■ ｃ，α ヨ ´ ■ ，Ｄ４ ｃａＯつ て ｃうｏ ”︶ 一ζ 一 ＱＯｏ一 ■ ｏヽ●●器 ●〓 ョｏ■ ざ ﹁ヽ ｏ３ 一総 マ 〓 ●こ こ α〓 ６ ０Ｒ ¨ σ〓 ＆ ０コ 〓 〓 ゛０ヨ Ｅ お 〓 ユ 薔 一 ，こ 〓 一 ■ 准 一Ｆ α８ 一 ´Ｉ こ 〓 ｒ に ■ ●８ ‘ コイ ョ ３ ” 彗 つらくＬ 〓 ＾ ぢ ａ ｒ ど ゼ 澪 ｃｒ， テ ︶ “マ ﹂ 一露 Ｒ ３ 准 書 ａ ０ ９ 〓 ｍξ ８ ８ コ ， ︶ ヨ ｉ ９ ３ ， 訂 ェ●０２″ 一 一 ■ ︵ く一 ヽ Ｃい 一ヽ０●， ０〇一一■ 一０一 一Ｆ え 〓 ´――― ― … ― ， 朽に ド に ぼ ｔ ［ 卜に ドほ に 時娼 ＾ ミヽ ほ ヽ 撮 長 学爬 ｒ卜 ヽ ド自 ﹂ ¨ ︱● ＬＩ い一′ ｃＤｃｃＦ ２ 一“ 〓 ” ０ ﹁ け ヽ ＞ ｒｒ ￡ ︶ 一 り９ ヽこ＾ 予 ２ 色 Ｆ資 Ｔ︵ れ雪講 一 〓 葬﹁﹂ 基調一 訴講一 一 咤錦＾ 中 ■年 中 ︶ 一 一 す﹁ ´ ´ ｏつ一 ´ ﹃ ¨ ´ ′一 つ¨ 〓 ン ＣＣ，■，３ ■ＣＣ ︵﹁ぼ‘﹁ ¨ デ〓ｒ２ｃａ 一 ´ ■ つ２ ごコ， ｏ 一 ︶で，′ ，﹀ ． 一 冒一 菱賄 祀鞣馨﹄ 要︵ 黎一 詳． 一 ポ・ 舞﹁ 憂一 一 一 工 ” Ｆ ■，﹂ 〓 ´ ０ヨ ｃ震 〓 “ ‘ ﹁‘′ ヽ´ ‘ Ｌ 一夕 ，ｓ， ｃ﹁〓 一一 ‘ Ｃ〓 ´ Ｆ ﹃ ●α一一４ コ´ｃ一 ●ａ ¨す０ ´ｃす・ ■一 一 り０ ﹁一 Ｃ一ＱЭｏＣヽＣンつ０一Ｃヽ， ］︶ ｏ コン ●一●一 ｔ一 一 ご ｃ 一 α ８ ， ‘ ，２ ｃくｏ ● ０３ ●‘● Ｃ● ｃ´ ，ａ ´ ■ 一ヽ ′ｃｒ´ ¨ ■ ´一言 ●う∽ご ´ ＾ ， ︶Ｃこ ´ ¨ご ラ， コ´って ，ス﹁０﹁７ ・ Ｃ‘‘一一 “ ｏ‘， ●●一ｃ、Ｌ ，、︵〓 つ・ ´ 一´ヶ一 ＾ 一 ′ ， ａＣＣ ■ ︶´ｃく０﹁〓 ０，Ｅ′ｃ′ ∽ＣＯす ¨ 一３●０ ３ ＾ ヽ 三 ■ ， ■，α ヨ ︵ 〓， 一 す ” ■ ′３ ■ ｃつ８ ， 、 ざ ワ ち ﹁■ ■ ＡＵ 一３ ， ﹁ ‘争 ︶ つ一 〇０ ， ︶つ´■ 一 ３ ¨ 早 ﹃ｏ一 ． 零議´ 薫¨ 一 一 需¨ 肇 巽 五一 笈ｒ鶏 一 噺条 ¨託 一 一 詳¨ 一 １ ご〓 ︰ ３ ´ ョｃ ２ ■ ８コ 〓０ ´ ” ｉ ■ き ヲ 許 言つ 檜 う〓 〓 ﹁ つ ，つα 三 一 〓 て Ｃ Ｆ ｃんや●， じ〓 て ， ヨ ●〓 ９ 姜 ■ ｃ ８ 一 一二 〓 ｃｃ ●■ 一ａ ｒ ＾ 〓０ 一 Ｊ● α●Ｃ〓コ一 ココ ︶﹁ 一 ョ“ ´ コ“ ●′つＣ，０コニＳ一 一 ●■っユ ＾ Ｃ ＾ つつヽｏオ一 こ考 Ｆ 一 〓 ３一 ｔ ヨ ●〓 ３ づ 〓 ｒ ヨ ー ■ ・ 〓 妥 ョ ｃ， こ ‘≡ ，´ラ 一 ″ＯＣＣ一 一 一 一 一 一 ，“ ●，‘“。´一一﹁一 ´ ´ ´。一 ´一¨ アＣ‘ ｏ ヽう０ ３，一 Ｃヽ¨ ´ ＣＣＣ﹁一一 一０¨ ´ 一 く´ Ｋ﹁ 二 ＞ ﹁‘一“∽ 一 ，︶ コ， ‘多● ＾ 一 ゴ● ■ ７ ■ ●● Ｌざ一 ‘′ ｔ ，一 を， ｔ〓 Ｃ ｒ︶一 翼 一ガ 羹 一葬 ﹂ 嬌表 ポ 〓 。 魂 多 ｏ 張 罐 一一鷺 ﹁ｈ 一鋼 ． 謙 ″⊆ ヨ ｃ ヨ ´ びヽ ０２ Ｚ ｏ 一コＬ ﹁ 一 ´ 〆 つ﹁ ｏこｃ， マ一 ぐ 一２ ｏｏ′ぁ ´Ｃ２´，一 そ ０﹁ 〓ケ 一 一 ０一一 一 一一ｏし， ｏ ●●″● ｏ●﹂ 〓ｏ¨ ¨ 一 ●′ くｏヽｏ ００３，ヽ■ヽ０﹂ ｍｏ●う０●一 ■１ 〓 要 “ぅ 揮 ” ¨ ■‘ 萎 堅 条 勇 輩 讐勇 一 ｏ フ 一 ヨ ｏこ色 ‘シ ｃ総 α ５ 一´〓ヨ 〓 ｏ 多 一 ５ ０ ０３ ●ュ 〓 ８ ４ ，Ｄａ ，Ｃ一一 す ７３ Ｃ一 だ ︵Ｏ ＞ ｒК︶ ｔ ， ３ ” ， ﹁二 ”∽ ，μ ｏつつｏ落 ０ ５ 一 お ， ぞ●コｏ′ ﹁〓 び 〓″″多 會´ ‘ん ﹁ ︶ ｃ二 ａ ３●α ＞ ” 凛プ● す ｏお つ ｏ■ Ｌ Ｏ︵ 〓． ， ７ 一︶ ´ ｔ ︲ ０ ＞ ｒくも ︶ ヽ ︵○ ＞ ｒКン■ 一 営 ｏＯ つ゛ 言 ｏ゛っ で． ｏｒ一 ︲ ・ ´ ｆ一 お 召 ●３ っ一ョ “■ ， ３ ″ ｏウ ， 多 ｏ ５ ｏ８ ョ ０■ Ｌ ８ ４ ﹁ｃヽ Ｏ ＞ ｒК レ ３ 一０政 ︶ 一 ・ κ 。 ｔ ｃョ 澪 ・ ‘α ＞ ” ■一 つ”ン ﹁二 一 一●﹂ σて ， 一 ﹄ｔ ” ０ ヽ゛ ， Ｖ Ａ ， ︵︺ ●コ一０つ′¨ つ´ ゛ ｏ′” ′﹁０一 つ一 〇０ 一 ０ ﹁一 ，´ ０一 ０¨´ ﹁●つ゛﹃ ﹁６，一 つ●´一コこ ´ ‘∽一 ●′ ︶ｏコα そｏ一 ● ●７● ョ Ｏα ■ ●ヨ ｏ３ ２ ユ ′ｏｃ﹁ｏ●´ ︵﹂ｏや ´コ ″ｏＯ ︵ ﹁ 手 一 すｏヽ 一”∽ ‘ ０ 〓Ｆ ﹁〓 ‘﹃， コタ ● コ■ ，ンア ，′ ︵ 一ｃ〓 一 Ｘ 〓 澪 一 て一 ′一 ，ｏα 一 ﹂ ，Ｃ つ一ｏＯＣＣ一 ，喧 ｏ●， ・ 一 ｏ﹁ ０一 ｏ一 あ ‘ｏ﹁０ ●ァ¨ ●一 ﹃ｏコ︺ 一 一 一 ｏ一 ︶ 〓 ０スｏ 〓ａ ＾ ﹁︶ヨ ｏ■ ２ Ｌ ﹁＾ ０し，´Ｇ￡Ｃ●ュっ０ っぅ０， ４´ ，一 ち〓 ｃ一 ヽ ０一 ﹁・ ¨り”一 ヽ一 に い ゞ ■ ・ｐ やヽ 嗅い与さＬに一 ， ︱ ヽ﹂曖ほ 降 ゛ 喰 た﹂︵ 腱 “崚に 曖 ﹂睫 ﹂楔 ド ド トト， ﹁ Ｌ に い一 ドドに に 婚 ■ ド に ﹂に し に ﹂ ﹁嗅 ” ト いｔｔ ＾ ヽＡ ｒ 一 塗 Ｌ ヽに ﹂ Ｆ ︲︲ ， ︱ ー ー ， ︲︱ ︲ 撃鵜 覇一 一 一 ﹁ 一 峰 一 一 一 詐 ¨ 算凄栞一一 一 一 錦理 議¨ ギ が 弱 議 お． 雲” 卜萎 ご藁 輩 ´ ﹁ 糧奪 程華難一 ３ 難 舞犠 詳中 講 疑彗 覇婆舞輩羮筆委聾〓 奨ゴ中 一 一 ， ｍ Ｃ一●ｏα ¨ゴげ一 ｏ営¨ Ｃｔ 一Ｆｏ ¨” ∽ コ´”ヽ コ●一 う０一 ３“ Ｃス一●ュ Ｃ，０〇 一 α■ ， ︶コ〓 ”一 営 ０一 ■ 一 記 つ， ■ ，■ ８ ¨δ コ 〓 一 一３ ， Ｐ 争 ご ０﹁ ヽ け０い０一 一●′ Ｃ´一 ｃ ０おτＯア＞〓ゴ ＪＯコ ｔ ヾ″ 中●■一 ン ， ３・ ｃョ。Ｃ﹁。﹁﹁ ｃ ｏ ｏ ■，０ ｏ” つ﹂ “ 〓´ ０ ¨ 〓一 一コ一 一 ヨ０﹁﹁ くｉｃ′ｃ∽︶一 ■７ ● つ０一 ´ コｃａ ●一‘ ﹂“ｃつ● ︵〓ｃ”，一 ． ，く０一〓¨一一０コ ﹃ つ﹃ ∽γ ｃてｃ¨ヽ ０デ６。´ ０，マ Ｃ一●ヨ ●“Ｃ，一，Ｃ一０∽‘ ｒ〓０∽ 一 ， ｃ マ ｏＦ ヨ ‘ ｒ Ｌ ´ ■ コ∽一〓 ご ■ ， 一ｏｏ一 ，お α 一Ｅ ，′ヨ 一 夕 ● コ 市 ，ＮＥ ヨＥユ∽ ど′ 一 す０¨ ｏョ２ぉ ，¨ ３●∽ ●コ■２ヒＯＱＯ●¨ ●コ一 ｏ 一ｃ〓●´レ К〓 マヨ０一 ︺ 奨¨ 詳委“ 競 訴拝鐵離誇一 男 証一 一 ¨ ¨ 喫れ ・ びぅ ぃぅα ﹂﹁ ・ ヨい つ﹁ 二´ ｏ一 ｏやっ８一 こ● ｏ Ｏヨ﹁ｏ３６■一ａＣ﹁ ，ヨ ´ つ ⊆´ ﹂ 一 ． ¨ 一 一 一 一 。 Ｃ 一 ﹁ 響 一 一 嗜 ¨ 〓 一 群 一 〓 一 一 〓 一 一 年 ％ ¨ 一 一 静 一 ﹂ デ 配 禦 ０ ィ ● Ｓ， α Ｑ︶ ン 一０´ ン 一 ヨ ■●く ‘ ，ｃヨ つっ 一 ﹁¨ ３ ョ こ只 こｃ３ｏＦＤｏく ‘ ご ‘ ＞ ”０ヽ ■ 〓 一 ン ● 〓 ９ ｃ〓 ら´ ﹂ヽイ ａ 一ァ ＯＦ， Ｆ´¨ェ 一 “●蛍” ■ 一■４● ｃマ ”二〓 ‘ ら コ一 ア ● く一 う二 こ こ﹁‘ヽ Ｌ ア ● く一 こ ｒ 〓 いぅ・すｏつ﹂ ︵ ︶ ■ ｆ 工 ”‘ 〓ｃマ ニ ¨ ヨ ヨ εス こ ■■■ ，ｃく´﹀，Ｃら ， ■ Ｃ ， ｒく ｆＦ 〓 ， と ， ｃ´″ ｏ 〓 ， くｏ亀 一ェ ０‘ ，れ，〓 一 ︷ ‘￡〓 お α ¨ 〓︶ ‘ｕ〓﹁ン” ， Ｔ，３一 ，１８，Ｆａ‘ｏ´ ●〓ｏうｏヽ´ 〓，お●フ ′ ３４〓′ ユニ■”，■¨ ■︼ ︵ 一ヽ中¨一ポ 頭 解 亜 碑 レ 綺 舞 痛 一〓 ﹄ 九〓 〓” 詐 一 縄 一パ ， ｃｃ多 ヨＱ ■ 〓 ８ 〓′＆ σＩ Ｉ こ ﹁ Ｊ ︰ 〓 一〓 ｒ 〓 ， 〓 α ７●０ やｏ３ 一 ，ｏ ｃ゛ｃＯ そｃａ ｃｃヽ Ｅ Ｄ４¨ コｃヨ σｃ﹁ｃ﹁■ ■■■ ●ュ ア 一 ェ０＜一 ョ一 静２■ ８一 ａｇ 〓∽ 一 デｃ 一 ムｔ〓ョ″ ﹃ ■ ｃ 〓ｇ′ ● ¨ ● ■工 ａｇ●一 ﹁一 イ０﹁ 一 ´ ′″ 一 ′ ´ Ｃ 一 一 ︶ ０一 Ｃ¨ ｏ´一 Ｇ‘●一 ︶ ′一 Ｄ“ 一 ﹃ ︵ ´ 一 ´ Ｃ´一 ＾ Ｄ・ ●´′＾ ●こ ヽ 一 ＾ ︶ ∽﹁ ２と 。コｃ 一﹁１ 〓〓 ３一 Ｑ●Ｄ営 ζ ３ ・ ９ 〓 Ｆ¨ 〓 ↑ 一つ０ヽ こ ０一 ﹄ 卜 ¨ で こ ミ ヽ一 や ヽミ ヤ与 嚇 難難 聾一 嘉一 一 華撃難毒″ 一 レ〓 く● ５ ´一 バ ﹁営 ｃ ｏヽ ０９， ｏ﹁〓 一ｏｏ７ ■ズ０一↑澪 Ｃ 一 ｏ すｏ ３ 一‘ 一■ ´ ■ ｃ﹁０ヨ ｃ混 す い つ〓 すｏ”ｏ， ョ３ ●７■ ｃ澪 ，ヨョ■ ヶ一 ン，コヽ 多 ， ｏ ﹁一 ３ ３ そ Ｎ色 二κ 〓だ ｏ， ９ ｏｒ κ ‘ ユ じ Ｉ ｏ， 一 ３ 〓 Ｊ ・４ ｏ ■ 一 一′ ゛ｏ●●Ｌヽ一 Ｃ， Ｏ﹁﹁ し く”ヽＦ︶ Ｃ゛ 一 ０〇一０﹁∽ｒｏ７ く，ュけ，一 ↓ 中´いヽ 、 、 ヽ ・ へ 、ぁ ． ヽ いく い ａ ｒ ヨ ， ３ ｏ汀 ■ ョ ヨ 一 Ｌ Ｏ﹁ｃ二 ｏｃ´ Ｃ●´Ｃ ■ ｏ﹁ｏ “ｃヨ ョ ”﹁ヾ 。ｃ ｃ● ¨ゴＣ σ●４ ● ︵ 一 つｏｒ一 ′ＯＣ﹁Ｃ一゛ ︵３ ，〓 ｏ ■︶ ゃ 距 躊馨 三¨ 勇” 第評糞 謙羮一 駐 勇島 〓 一 ︶ ・ い ０ いｒ く ０い ｏヽヽ ，″︵ヽ＞一 ● Ｏｏ４い００﹁０●゛Ｏ Ｎ芍 ９ＶＯｏ０ ０， どて ヽ００、 ζ ゛ ｏヨヨ‘Ｄ一 Ｃ一 〓し″ ζｐ ＯＲ６ ０Ｌ ■■８コｏ 一σＦ ω ２２・ た０コヽ ︵ｃ一 ６３ 一 ６ ０■ ８一 ３︺ 一 ■ｎく ｏヽェ一く ０，■ 一０い● つ０ヽ０”い０ 工 Ｏｎ 一し ＮＯｂ ０ ０ ﹁⊆ ヨ ヨ ●ユ ， お ， ０ コ 一い ｕヽ ９ｏ０ 全 RtR 一 ９ ヽ ｏつ ● ＯＮ ８ ｏ ｏつ︱ コ苺 ¨ ８ 〇 ０３ ２ 一 ぶ 、一 ず創劃計劇＝創＝４ず﹁﹁ 琉鐵帯到難謝瀞乱轟璃 ■■計， 一 ﹁”い 一露 ︵一 話 ¨一夢 ︵ 菊 “ 一 聾 一 沖 一ｒ 葬 努 ２●ε ﹃ ■ｏア ■●つ′﹁ う ｃ′‘〓ＯＬ 一 ，４。３ Ｃ一一一∽ つ一 ２一 ０す●´。 ぃ ｏ〓ぅな〓 一 一 レ一 一 ︼ ●ｏｃ一 ｃ‘っコ ﹃ ●●´ 一 一 ＾ ■´ ｃ・４＾ ｃ ´ 一 ´ ′﹁ Ｃ，コニマ ﹃ ヽ ４“コ一 ＣａＣｎｃＯ ﹁ ﹁ 一 一 Ｆ 一 ， ﹁ け 一 〓 く 一 一コ゛ Ｅ´ｏ■ ﹁ Ｃつ０・ りいデ 一 〓Ｅ´ ﹃ 一 ０ ０〇一一 ′０ ０ ﹁Ｃ ¨ ¨ ′´●一 ３一 ´ 一 ↑ＯＣＣＣα ∽一 ヽ一 ３¨ 一 一ｃＤ″ ヨ ●︶ υ ●﹁ｃ一 ´４Ｃ３ ｏ﹁二一 Ｃ 一”∽ 一 Ｃ﹁ コ■， ュ事 ゛ｒ ３，マ 、 ｃＬ〓ｏ■ 一Ｆ● ●■■声〓´●一し〓Ｃ“Ｃ，Ｃ一 ｏ ｏＦフコ´ ９﹁ ﹁ ｏ﹂ＣＣＣＣ Ｃｏつｏｃ¨ 澤 諄 ●８ ●Ｉ 雪 ′ご 争 ︰ ‘ ３ こ ご 杞 〓〓 マ ‘ 〓 ３︰ 卜” 一 ヽ 一 ヽ ｏ ヽ ヽこ ヽ 一 ” 一 い一 ●一■ ヽごＣ♂ ｏヽ くヽ一 ●一レ ヽ一ヽ ヽ ヽマ，卜´ 、ご 、 ′ 一 ド´ ヽ ヽ ヽヽ ヨ ミヽ¨ 、 、 、´ 一 ・ ヽ 一 ” ´ミ﹂ ヽヽヽ一 ∞〓 Ｆ﹁ ヒ 揆ぢ 〓ヨ〓二ざ● デ ｏ貫 澪 ２一 〓 ｃヨ︵ ０●オ 一 ４ ０お く，一 ●ユ ︶ ヽヽ ¨ “ヽ 一 一 ︺一 一 ″ ¨ ，一 〇０ ´ ０一 一一 一 く〓〓 ∽Ｃ‘‘ 一，こｃり一﹁ ∽ ●０一 一 ，一●ヽ ｏ３ ﹁ ´ ′ つ一 つ一 Ｃ％一 一 一 ダ 一 一 ， α ∋ ３ 魚 バ ∽ ， に ， そ こ Ｃ ュ α Ｏ こ う ２ ２ ｃ ´ ，∽ 一 ， 、 コ ﹃ ● ２ ︵ ８ ョ ｏ ﹁ ｃ ９ ３” ｃ ′ ｔ＆ ８ｆ亀ぉ■るコ つｏｃ ′ ｏ一 ´ ｃヽ ， ， つ マ‘０３● Ｃ ‘ ＆ 〓 一 ∪﹁ ２ ９ ａ〓 ﹃ 工〓 一 ９ ２Ｆ テ ﹂ 二 ぁ 却´ ﹁ こ ＞αヨー ニ ざｃ∽００ｃコ〓″´，つてｏくｏ，，一 ´ ｏ﹁ ●コ一モ〓，２一＾ ，■〓一 ︶す くヽ﹁ ，一 一 致難 税 華一 華一 轟響面 綱 一一 一 ＾ 一 嗜 ↓ 継¨ ¨ ¨ 一 野・ ¨ ¨ 一 一 ︼ 緯輩 ¨ 押 ¨ 三難露一 巽］ ¨ 務 撫﹄ ¨ ｏ ・ 輩一 ジ藁¨ メｂ 嗜 導鶏幕 繁装﹂ 一 ¨ ¨ 誕諄 誠一 誕寵¨ 一 奪・ Ｆ 競 市 奪 軍 野 ︶ 警疑畔 憂一 語辞 ≠ ﹂ 霙表 計摯 蠣． 費弓 一 黎 メ． 摯 一 誕聾一 一 ¨ ２一 ″ 警 ３ ●′ ∽ 手 ョｏ﹁ ε〓ｋし く ，ｃ●９ ■一 ● ｏ■ ９〓●ユ■■一 ¨ ち〓ｔ´。■ 輯¨ 希 繁零要藁藁¨ ¨ 菱葬 れ 一 喜霙喀 ︶ ， ”●゛ ″ ‘一 ％ヽ２，いｏ ヽ■ミｏ ２ミ 為いヽヽ ● ξきヽ ∞´レコ 一 ﹁す く 営■↑一 ｊヱ＾ｉ ，〓〓 Ｌ ● ● ｏ ｏ ６ 〓ヨ ｏ一 お′ 工■ ‘ 。 一 叶 ■一 ギ 弓¨ 中 ¨ ﹂ 聾 郷︵ 一 郷 雲一 郊 ♂ ¨ 一 ﹃ 純 一 ﹂ 誠＾ 一 換群申わ ¨ ﹂ つＣ一 ＯＯ∽一 ﹁Ｃ一 ﹂二 ′ 一 ● コヽ一 ０﹁ ′に一 ●くｏ∽一コ´０●´ ‘● 一ｒ，一 一すｏ 口ａＣ 〓 一 猪 ﹂聟 一燿 ・ 一夢 謹 一一 ・ ︶ 。 ︻一”高〓一一 ¨¨一は一一一 ¨¨″﹂い ﹁一 ¨一﹂一 ″一一 一一 一 ¨﹂み〓¨ ¨”﹂¨´¨¨一¨¨一 ´ 一 Ｃぅ¨ ´ つ”一 難 一 こ 華撃彗導 一 輩。 一 Ｎ∝一 ︶ ． ０＾ ¨ ´ ´ ０￡ＣＯ，０●，一 ． ″ ， ，ＦＡｏ■ 望Ｏｏ。ご ∽ ヽヨ い ０９ ´０●一 ︲ ｏ﹁ｏ■ １ ３ 惨 ζｏα■ ■一 喘ド 一 ●ざ■ 澪 ●９ 一 日﹂﹁ 日電 Ｆ語ＦＬＬに階︱ ︲１ １ １１︰︱︱︱ ︲︱ ︲卜 ・ ︱ ︱︱︱︱ ︱ Ｚｏ一６０， ０ヽ３ 一 ω∞０∝ 鍵 一 〓 “ いら´ ｏ， ︶ ﹁ ■ ●コα Ｅ′ ●一〓 ｃ一 ｃ ，ぢ Ｅ ヨ 〓 〓 ０こ ２ ｃ¨ ０ァマ ︶ 一ｃ﹃ ′ ”う０ ケ０コ■´¨ ■●■ ヽくュ ０，コうｏ ｏ﹁ ヨ ３ ﹁ｏ， ，３ α 〓 ９ ， ュ 一●グ一 ∽Ｑ‘ｏ ５ ‘ｃ升 ● И ヽ３０ つ澪 ョ 〓 ‘お ｃｃ● ゴ ﹁ξ 〓 Ｑ ■ ●Ｒ ´， ｏγ 一 ヽ ヽヽ ざミ ︺ヽ いヽ 、 ヽ ミヽヽ彗ヽ０ヽヽ ミヽ一 一 一 ″ ， ∽ ０﹁一”， ｃ﹁Ｆ 一ｏ●ｏＳ ３ ョ 〓 一 引γ ル●Ｌ イヽｏ ３ ｃ ｃら ０， そＯ ｃ∽Ｇα ３ ２ ８ ■ ３ ， ｐＦ マ ３ ８ ∽ｃ﹁３ 〓 垢 ●・ ﹁ビげ一●・ 一一Ｐ 二 〇 ， ︵９ 一 ＞０，ｃおいデ ０一 彗０一 窮 髯 Ｃ コ・ヽＣ一 ●一０こ 一ε﹁Ｃ ｏ●′一﹂ 一り一︸ ３′一ｒ′一 ●コ〓一′ヽく一 コに′ 〓´ 一Ｆ一 ●一Ｌ 〓 一 ´∽●５゛〓 二 ， ，コ〓 ， み て 〓 ｃ〓 ﹂ ６ ０■ ■ヽヨ す ０ ３ ｏ ﹃０ゲｃ‘ う； ％ 一 ¨ 一 ０ ヽヽコ“ｏ∽ す● ０´ ︹ つ情 ｏ一 ゛ 一 Ｃ′一 一一 ぃ 。て 一 ■´一 くＣコ●∽一，う●一 ●ヽ¨ ︶ 一一 ■一 Ｏｎ＾ ︼∽一 一 藁一 ﹁ 託三議葬弄勇一 ♭チ 藁套一 錦 輩 鍔れ 襲一 一 毒餌 碑 費凛導 を ・ ′ 話 ％ 壺 ■ 一 緒¨ 中中 ﹁ 野哨一 れ 一 聾 ギ 話≒覇諸製疑¨ ¨ 中 鷲蝉肇［ ． 一 ， ｏ ´ ¨ 一 計π 〓 ¨ 十 “ ぷ Ъ 麗舞 一 ﹁ ・ Ｃ 編ｎ 巧 〓ギ縄聾〓 墾一 勇 考珀 釜一 ﹂ 罐 議れ ¨ 議ヽ お華 勇［ 一 誇略一 霧 ¨ 轟 壽﹄菱愛一 ﹂ 躍¨ ¨ ¨ ¨ “ ｃ ｃ ＾ ﹁ 一 獅〓 〓﹂ 桑 ■﹄ 程 電一 〓 ｒド蒟輩 晰¨ ¨ 畳¨ 馨一 維﹂ 一 ﹂ ¨ く ・ ，つαＬ ‘ｃ ｃ′”３ ョＯｃ 多 Ｏ ｒｏ〓， ｏｏｏ３ｏヨ み ００コ●ｃｒｃｏコ●， ●一 。コ¨ 一 ご一■一 一 ”∽ 一 〓ゴ，■●ｃつ一 ︶ ｃＬ¨ ︵ う一 〓一 ｃＤ¨ヽ＾ 一 Ｃ〓 ０﹁一 ´ ｏ一 Ｃ﹃Ｌ ﹁ｃヽ 弁 ０一ヽコＣ〓 一 ａ 一 ゴえ，一 て一 一 ０ ，Ｃ¨ ヨ コ´ご ∽夢 ７ 〓 〓澪﹂ ， お， ， コ ﹁ 戸 コ 澤 こ ´ 言 言 〓 こ 一 １ 羹 ‘ζ ≡ ﹁ ３ 膚 一 君 ■ ， Ｊ一 やｏヨ 一 一 Ｌ 。ｏ３■ 一 マ● ０笙汀〓 〓 ‘ Ｄ ａ＾ こ′ 〓 ● 〓罵 ご Ｏｃ Ｐ ︶澪 コ一 一 ０ ぃ ０つて′ すｏコ﹁３一■４ョ ｏぅ ｏ﹁２ ２ ０こ︻，●ヽついｏ キｏ３ り 一 一４ ｏ３一一 ゴ０一 ０づ“・ Ｃ，，０００﹁０一 ０● “つ０ 一 ”，つ‘﹁ ‘゛一 ●一 ●一 ψ●”∽●一‘０´ ０ ﹁´ Ｃ´一 υく０一 ， 一 す ０﹂でＣ● ● 一くｏっ燃 。●●■ 一 〓﹁ ヨ ＯＣ３一Ｃ￡０こつｏＣ一 ●″ 。。ご ● α て 一 詭 ジ ボ 議 ． ¨ ¨¨≒ 繋 ﹃¨露 ８ ， ｏ ｏ●３ や０コ“＾ Ｃ﹃ ´ ョ●８ Юご ｆ Ｆ一ａｃ一ｃけす●く０パニκ ｏ２ おＯＦ ａ 一 ヨ つ二 ｏ﹂ 。Ｑ﹂ｏα ｏ●‘ αεｏ ５ ｏ２ ●， ０一０，ョ “ び′ ， Ｌ フ ア 一 つ、 〓 摯 び τ δ 二 ，αＱ三 ＾ 一 コ＾ く ヨ 〓 一， お お， オ し ｏｏコＦ ヽ ● ”粉 ｃ 理 う ■●一ｏコα つｏ´■Ｊｏ﹁ ォＣ一 ，﹃ すｏ●ＣＣ Ｃ， ﹁ ， ●コ´●０〓う一 Ｏｏ■３一Ｃ●一 ﹁ ０●一” ” ︺ ％へヽ ヽゝ 昼 ぜ ”む ¨ ●■ ■ ， ヽ ヽ ゞ ョ 〆 ゛〓ョ ｃ ，ここ ■ｃｒ ご ﹁ｉ ｃ ヨ 一 ■︶ ０●２ ｏいｏ３ ｏ弔 も ヽ ■ ヽｃ′●´ 多 ョ ｑ Ｏタ ヨ ” ュ´″ ∩ｏ一´ お ， オ ●コ９ ● ヨ ン お﹃ ｏ‘ｏ﹂ ョ ｏ﹁ォ●全 マ 娑 一 ｏ﹁ ■ コ′ヨ み〓ｏつ ︵ ョ，〓 ｏ ﹁︶ ０ 〓 ｏう ﹂一■ でｏ ■Ｌヨ お＾一０ ●● Ｃヽく〓彗 一 ｏ一一す 工 ︵ ド 弄 Ｏｃ３ ｏ■ 君 二 ﹃ ε ‘ ３ つヽュ 子 ■ ョ 聡 ２ て， ■ ■ 一 ″一 Ｆ● ュｏ一，〓●●´ 〇一 ●●●‘、コ”一 て一 ●´ ﹁ ，つ′ヽ ●， ｏｏＣ´ ついつ一 ●一 ●´´ ０一一一 ‘′一 一′一 ｏ﹁ 一 ｏ∽一 ０，′●∽ す一 Ｃ﹁●〓二い て一 Ｃヽ ●一 ｏ﹁ ●コ′﹁ Ｃコ 一 ●●一 ′一 “ ｏ﹁０●′〓﹁ 一０ゞ 一 ヾし ，﹁ 〓 ”コαａｏ う０一ぉっ０ 一 贅︶ ● ●３●一 ，ｃマ二三 ′ら ︵ ｏ，多くヨ ０一 、 〓 ■〓 ， つ８ ´ ｃｉ ３ ● ０﹁ ３●■ｃＬ Ｏ﹁ ●〓●ヨ ﹂ 一 コ Ｑ＾ ′Ｆ・３ ｏ，コ¨ ﹁ 一 ″ く〓Ｃ∽Ｃ Ｏｃ ・ ＾ く ｏ﹁‘さ‘ Ｚ 一 ●コ一３ 一 ′こ う ０﹁ヽコ エ 中 ﹃ ３ ，ム●∽‘ コ﹁ ４一一■ ■お ヨ¨ つ〓 〓●“●コ そ●Ｃこ ｋお こ ﹂零 菫 σ・●‘〓 一〓 おヽヨ ∽０﹁ 一一 ご， ●“α こ一 ●Ｏ ｏ●４ ，■〓Ｏｃａ ，３﹂ てＯＣ一 マｏし， ¨〓 コｃａ ，コ﹂ ヽ∽∽ｏＬ ｏ一 ご お ２ を 一，９ ￠８ ¨ ５ つ ごに ，ｔ ，， ｃ８ ヶ″ ，︶ ∽一 ■﹁ ・ ・ 鋼 観 葬一 緩 筆 難豪 葬難墓飾 一 一 ヨ 〓げ一 ●い ００■ ｏさ 〓 ■ ３ ， ２ ， １ ●３ ３ 一 ｏ８ ぞ 一＾ ８ 年， さ ヽ ０●一 ヽヨ ５ ， ■ ● ｎ９ 一ゴ Ｆ Ｄ Ｒ い０ ５ 一 こ ＞α一 ３ ０． ｃ´一 ＞ｒｒ Ｚ工ｒ ９ 下 〓 Ｑ ０３ て い９ イ Ｉ Ｑ α， ｏヨ〓 一 うＤ”一 て，一 ０，い 一 ０一 ●０ ∞”一 ２，う０こい，お，Ｒ 一， ０ヽσ，Ａ■一 ●二 ＬＬ ， ｓＦ ミ 一● ９８ ８・ ８ ｏ ●３ ８ ０ ３ ８ ０ ＮＱ ｂ８ ︵＞”０ ェ● ＞ヽ ， ０ 〇一 まぐ ０９ だ ０﹁０ こ ζ 〓 ヽ０ ´ δ貿 ・ ０ こ ‘ヽ ｏ３ ●コ ＮＯＰ§ 一Ｑω・ ８ ｏ 一ｏぶ ８ ０ ００ い ０ ９ｏ 一〓 ２，６０こい０ヨｎ配 ，いヽミ 一К●コヽ０ 一 、 ９９，ｖ９ ”００Ｒ﹀ ヽ”ｐＲと ヽＯＮＲＯ 一ヽこやＯＹ０ Ｓい 一 ≡ 〓 憾 ⊃”ヽ ０一 ３ ■ ︰ ヨ●計 一 Ｏ ｔ ● ８ ｏ ︺０８ 〇 一ヽ ８ 〇 一ヽ ０ ８ ヽＯＮ・ ８ ｏ Ｒ・ ． ■ コ ， ｏＥκ コ０゛ ｏ一 くｏ， ヽ ｏｃＤαｏα ＞ ”ｒ ， Ｓ ｏ●８ い ●Ｏｃ一 ０ く ３ ０す００■ ● ″ ｃぇ●３ ， 一 Ｚ ェ ｒ うＯＰ ェ０〇一ヽ コ ´ ギ ３ ０す０ヨ Ｐ Ｏ＞ ９０ ・︵ｏ﹁ ｏコ一２ ●■●Ｑ 。て０、′ 一 ” ３” ヽヽ ∝、 つ ｏ′´ ん 一〓 ２ ● ｃ，９ ′ Ｅ 一３ 一 ｏ＾ 一′ ３ ，４ ３ お ﹁﹁〓 ″ 一 〓 褥 て 一 コ ﹁‘ ■ Ｄ〓 一 井 ξ ´ す●ィｃ Ｃ４ 一 子 一一 ´こ 〓 ｒ■ ■ コ ， 二 ｃマ ３ 一 ′〓４α ， ＣＣ， ・ τ ｃ，〓 ﹂０こ ﹁いｏコ一 ∽り， こ こ ０ ︵‘︼ ，■ ¨ し 一 ● ■ ¨ ■３ ”〓 “ 一■〓 一 〓¨ ¨ ′ ． ・ 一 十 ﹂ 一す 一〓︼ 一 ¨¨一中一一 中一筆 ¨に 一¨一一一ユ ¨一 ﹁¨一一︵ ¨ 一一一一一¨一 ， ・ ¨ ・・ ´ コ●イｃ ａｃ″ ﹃ヨ ， Ｆ ｒ υ〓 ２ ■ ■ 一澪 ■ 一 夕 ﹁ ｃ＾ ツ′一● ■ に■ ● Ｃつ， 多 即 〓 Ｃズ，コ´一 一 α ■ 一３ ︵３Ｃ ｒ，■ ︻Ｃα ∽ ｒ二 ｃ゛ 一 コ＾Ｃ﹁´Ｃコ〓 Ｃ コ﹀ ＾，■´ ︶ュＣ一 手 ち ⊂ョ ３ Ｌ ︵ ¨ ︰ 子 １ １ 〓 ３ｃ′ 二 ３ ２ ヨ 碍 Ｊ 年 ０ ＞ ︻く ”二 〓 α 〓 ０ ■ぢ ´こ ■ ｃａ ｒ■ ， ヽ ＾ ︶ 〓 〓ｃ＾ ご こ こ■ ５α多 ＾ 〓 ， ，２ 一 ﹂ イ 一 ３ ■ ｃヽ ● こ Ｊ だ ″Ｊ 一 ＦＬ スＦ 攣 一 ヽ ¨ ¨ ¨ 葛 ・ とヽ ３ ¨ ■¨ 一コ‘ 〓ｒＦ ´ 一 二 ︵ 〓一 〓 ﹁ 一Ｊ﹁ 一︰●﹂ ´ ，一 口′ｃ２ ″ ３●， ｃ´Ｃ´営 ４ ３ 一 ｏ′Ｊｃ一 ． 一 請 要 れ姥 ＾ 一 ン護ｃ ％ 〓 ■ ﹁一 姜´ ”奪 ¨ 罪一 讐一 ａ Ｆ ８ ，１ 汀 一 ヨＳ ‘ ﹁ ， 多 〓 ‘ ョ κ ｇ ３ ョ つ一 α３３ 一 〓 ｃ〓 ■ Ｐ，■●つｃ′ ﹁ 〓す´ ミ ● ヨｃｃゴ ，一 ゴ，コ 〓ｃ ｏ， ご景″ ”ゴー 一 ●笙 多 〓 ゛コｏこ′ ついち，一 っ＾ ， 一ｏ●■ 一 浄 ■ ア ２ マ ´ ん ２ ｏ 〓 ● ｃ ′ ， ■ ｏ ｏ ウ 一 ０こ ﹂ｏ﹁〓ＣＣ 一 ヽコ﹂ ′〓ＣＣ一 Ｃ 一 コ，“﹁●Ｃつ ＣＣ コ´つ，■ ，Ｖ´′ 一コ Ｃ二´Ｃｉ ■︵ ´ ´こ ´ｏお ¨ イ ａ´ コ０そ ７一 ＾ ＾ マ ″ ｃ，ヨ ンδ ﹂ ｏ， 多，ｃ二 α ，ｃ ●く２ ｃ●８ ０ ，“”ョ ´一ぉ ｃ，言 姜 こ ″ ′ 一 ・ 多 ４ ，´ ヨｏ ¨ ¨ ﹁α， → “ Ｚ ＞﹁ ′ｏ，ｃｃユ ●“ 〓 コ ■●〓 ヨ ｃつこ ﹁一 ユ ヨ“●３ ︲ ３９ ０〓 ゴ＾ つ〓 ′一 〓 ブ一 ｃａ´ Ｆ ●３ ョ ，， ７ 一一 い”´︵ ＯＦ雙 ０ ﹁■﹃Ｏ ＞ ｒく ︵工︵く Ｚ＞﹁ す ﹁ ■■，ｏｃ二 “ヽいと 〓ｏ‘﹁ ︲ ・ ，¨ ■ ′ら ｉ， 一 ｃＤ τ ′αＣＣａｃ一 ３ つヽマす ■ すｃＦ ３ ● ２ ｏ■ ， コ′﹂´ 一 ´ ﹂ ′０﹂ 一 一 ´ ＾ ︶ ＾ 一 ，一 Ｃ﹃ Ｃ´一一 ＾ ０一 ¨ ´ コ﹂ つつつ， Ｃ つル、 ¨ ´ ●´ ＾ ´ ３一一 ︶ マ ｅ´つＣｏ一 一 ，一 Ｋ一 一 ご イ ■ こ メ ″ ぅ 争 そ ″ 言 つ〓 ュ 一ｏ つｏ， ‘ ● 一■ ヽ ︶ ′ｉ ＾ ョ・ ３” ｏｏ＾ ■¨ ′ ‘ ﹁■ ´ 〓 〓 ﹂営 一 ● 〓 ｃ ｃ 〓 く ｏ コ ‘ ι′ ヶ ﹁ ニ ンＣ 一∞ ∽ 一● ａ ｃ ﹁一０ コ 一 ‘ 〓 ｃ 一て コンｃ ¨ 一● コ 一 ﹂ Ｏ ｃ アｃ 一 〓 一 ∞´ ヱ ２ て， く つｃ Ｃ ′ つン ‘ ε う ｃ﹃ ｏ ｏ﹂一 Ｏｃ つ ‘Ξ ，´ ‘コ ■＾ ざ ● ヨ つ〓 く２ ニ コ情 〓¨ ■ ″ ｔ ンに ヨ Ｆ ｌ ■ 一一 〓 ｃｃ‘ ・ ︶ ５ ，ご ′す 一 イ α一 ユ一 一﹁，コ′コニ，一﹂ Ｃ一 ′ｃ，′↑ 一 ●ヽ 〓´ ■ 一︶ ︶ ︵﹁一 “Ｃ一 卜 υ ア●●ι 一 ●ヨ 一 ヨ ｏ一 ■ し●●，４´‘ｏ ｃｘ●３ ５ ４α 〓る ６一●■ ︶ョ 〓 ョ一つ、， ｏ一ｔ´一 汀 一∞∽ 一 ●一 一 コ ど つヽ 一 つ ´ぉ ｃｔ ョ す ｏ﹂ ， ■ 一 ， ｃ ，， ｏ９ ¨ ５ ， す声メ︶ ＾、 ●一● ｏ﹁ 一 ，Ｃ ，¨ こ Ｃ一一一 すｏ 一 ｏ“︼ ●３こ ¨ ｏ，α‘﹃ Ｃ、 ＣＣ，つ０一 ， コ′ ユ ｃ‘ ｏ一 多 ｃ ︻”∽ ７て ， ● ●﹁，︶ 〓ｃ〓 多 お ，■ 一 ヨ，一 ８一 ′， ． 弱 請 請 一撃 輩 ” 一増 要 凛 一託 詳 幹 醍 雰 ″ ´ ′ヨ ｃ １ ‘そ３“ 一 が 講一 一 ﹃ 一 ¨ 訂三七 一 語聾 夢露酔鷺一 一 一 残一 一 一 ↓ ■´ 一，コ０一 Э﹁ｏＯＬ〓一 コン一情，， ｏグ¨ ´´‘Ｃず つ′ｏて，︶ ，一 ，・︶ ●●り一一 ‘“， つ´●一 ・´ ， く︶′ 一 α〓‘′一 ︷ ・ ｃ ﹃・ ヨ¨ ﹁ ﹂コ ご■，●︵ Ｃ′ Ｄ ｃ ｏ ﹂●ｆ‘′・ “ ｃ ﹃ 〓● ︼ 鋪扉 巽﹂ 葬髪発¨ 一 ︸ ﹁ ｙ雰言一 ｏ ｌ‘ 一 一 ﹁ ′ ﹁ 〓一一 ”¨¨︶ 輩 “ ﹂ 〓 稗 ≒ 鶴 ¨﹂ 島 き ¨ 一¨〓 押“ 室 ﹁ 表 ︷ 〓 驚 一 詢 ″ ・ ＾ ´ お ， 一 ＣＣ ７ 一 ０ル一 ＣＦ ﹁一三 : ●コ０ 一一Ｅ 一 ■ ■ ´ ■ ， す ● ﹁一 一π∽ ４ 〓 、 三 一 ・ 一 ´ぉ ４・ ︶ ０ら ｃｒ´一 ・ ′●●ゲＣａ，つオ● レ′ｃｉｃｃコｏ ●一一マニ‘ ０ ＾ ¨ ‘↑ ■っ、 ，ェ 一 ´ｏ一 ︶一 一 ′´ Ｃ一 ＾ ´ ００∽ リ 一 多 Ｃ¨﹁Ｃく一 くＣＣ ′¨ ピ０一 Ｃ´ 一´ くｔ一●′′ ﹁一 ︶一 ＾ 一 Ｃ´ ︶ フ一一 ■﹁ヽ ＣＣ¨ ′ 三年５ ４〓一 一 ＣＣ ´〓´一 ¨ｏ﹂‘Ｃ一 つＣ ´ｙＣ ３‘・ ヨすα一 Ｃ一一，一ｉ Ｃ，〓ｏつ〓一一●〓二´ 丁 ａ ７● ＯＦ ´ 〓う´ 〓 こ ｃ■こ′ Ｚ ｏそ ■ ，コ資 ‘Ｌ Ｏコ ´〓ｃ一て コ一， デ Ｌ﹁ｃ′４´●⊆一 ，﹂一 〓﹁Ｏ′，３一 α′ 一 Ｊ一 ●ら二´Ｃ一■′′ ´ ´ Ｆ二Ｃ一 すｋ 〓′ｃ γ一 “，Ｃ一 〇０′，Ｃ一一 ，一 ■ＰＣ く，一 Ｄ“ ´ 一 つ一Ｃ〓， Ｃ ′０■ Ｃ一 ｏＣＣＣ一 ＣＣ 一 ｏ３一４一 ■ｏ●ｃ，〓ｃァ ﹁ イ っ、 ﹁ ヽ こ 〓一 キ ヨ 〓 ａｒ ｉ ′ ■ こ 一 ｃ ヨ´ ︶ヨ ， ３ 一コ 一 こ ‘﹁″ ´ ■ 一 場二一 ■ ヽ２ ・ 一 ´ ′ ，´ 一 ， ァら 一﹁Ｃ‘ ﹁コ︶﹁´ ヽ﹁ ０〓´。﹁ 一一 ＾ ｒｏＤ一 一 ●Ｑ 一 一ｒ二●ｃ´ っ一﹁・ ′⊆う´ ｉＣ，ュ ﹃ Ｃ，一Ｃつ′ Ｃ一 〓Ｃ色一 柔一 輯ら 十 勢勇” 一 一 一 聾島一 一 費︶ 誠お． 一 ３一 一 れ 一 ゴ●一只 ， ７Ｃ〓ＣＣ〓く一コ‘︶´ 一， ”﹂α〓〓︶ コ コニ３〓 一 う・´ Ｃ コン●４ す０︵ 〓 一 ． ′ 誇 詩醜 ヤ一 三響一 〓 ” 章 一 葬■ 一 ︼ 一 ¨ 構摯 一 誕こ ︼ ¨ 一 一 Кヽ すＦ ヨ■一 ´ ”ｃＰ ■ ヨ８ ′ 一 譜行詭 輩一 疇議配 華． 一 算＾ ¨ 芳勇一 ″ 勇” 黎一 社 一 義´ 一 ｃ，■ ‘一 〓 ′´一 ィ〓 ■ヽ ｃ一 〓 ヨ〓〓 ュヨ ｃつ０こ■´ だ つ●〓 ′ ︵ ‘〓ｒ ョα 一 雰 一 ■ 一ヨ■ Ｔ ｏＦ 三 ｒ ｉ 〓 一 一 〓 三 ■ ３ 〓 ｃｉ え て３ ‘ Ｒ 〓 〓 ● κ ョ 一 、 ． 響 海〓夢膚＾ 一輩愛一 〓■↓゛ 〓一 三´ 盤 彙資 “ ι ｏ好一 ´ 一 年 一 一 一 ︿ 〓 “ 一 語 聾 年 一 発 中 舞 熊 一 一 〓 一 一 一 ﹄ ル ﹂ 一 一 一 一 一 一 計 キ 一 ¨ ﹂ 。レ ´ ＾ ´¨ ︶ ． Ｆｆｌｌ レ“ ′ ■． ■ ｔ “ 好が一 一 講三ａ ｔ¨ラら 一 軒薦”一 〓 聾¨ ， 一一一 ″一 ´、 〓一一一 一 一 一 ］＾ ％ヽ７ ′′Ｌ 、 ︶ ヽマ ヽ寸ヽ ヽ ヽ 一 ヽ ヽ ヽ ﹁ ´¨ 一ヽ ‘０︵ ア ” くィ¨ ＾ ３ コｒ 一 ン ■一 ■ 一コ ０ こ， 〓 プ一，Ｅ 一 フ 〓〓ら２ 一 ＾ 名 〓 ヨ ■ ″〓 一 ぢ ´５ ´ κ，一 アウ，こ一 一 ´ご´′ミ一一¨０こＣ▲¨ Ｃ´〓〓¨ ． ル筆■輩語葬雪菫・ 毛一 一 勇諏ィ ダ︼ 菱誓 〓 一 ε Ｃ一 ，一 一 一 末イつ一 く一 一 一 ´ メ︶ ゴ＾ ´ ゴ´ ＾ 一 Ｃ¨ ¨ ﹁ Ｃヽ ´ ´ ´ ﹁ ＾ ︶一 。一 一 一 ア●一 ﹃ ぢ‘一 ＾ ¨ 一，Ｃつ一 一■ こ″一 一 ′７一 一、 “、 〓 ヨ ＞０一一，こα ‘ ，く０“ 一，ｒ Ｏ 雪 ３ ３ 矛 ξ ●ミ Ｉ Ｉ 〓 ζ ョ ヽ ・ ξ 〓 ヽ一 〓 ゛ξ 誕輩¨ 鉾 詳︶ 〓委輩勇亀． 蟄一 三界率 春 Ｏ，● ■，︺一デＮ、一 勇 界告 姜・ 一 ¨ 聾識 講宅 ¨ 一 蠅一 三 評調諄¨ ＾ 聾葬 ． 築” 豪 竜菱輛¨ 一 月護輩≠巽ネ 響一 ︼ ． 勇三嗜聾ヽ 準 勇こ詢一 薫 責一 響 羹妻一 一 一 鍾疑・ ４ 一 基＾ 一 鍔 一 一 一 零 賀一 聾 一 請 ﹂ 鋼 多 一 調高 霙 一 一 ﹂ 葬 一一 一 理 営 弊詳詳詳罪一 議 一 多 ´ ¨ 髪狂鷲 一 勇華﹂ ¨ 一 一 萎 葬 毒 暮 華嘉一 華藝一難華一 や ， く ． ■〓〓ヨ´ ＾ ３ ｒζ ６‘ｃｃコ３ ，営 ズ ，一 ，す ﹂● 十 ´ ‘ 〓 ”ロ コ″一一鸞 ”∽一 ｃョ０ ェ”く 一■︶ 一 ェ”く ０′ン 一 ｃ‘３” ヨヽマ つ〓 ィｃ， ´ ヽユ ■〓つ０ ，一 Ｃ，Ｐ，、二′，■０， 、ヽヽヽ ヽ ，〓¨ ヽミヽ 一 ■¨ ¨ うあヨァ‘Ｃつ７一■つつ４こ´，コ ︲ 業 誇 : ξi く〓 〓■ ヽ長 ，く、‘Ｆ 一 ８ ９８ ８ ６ ８ 〓 ８ ｂ ”︻ 昇一 一 Ｊる こ一 ゴ３一おョ︵ ＾ ぢ Ｒ Ｏ﹁ζ ∽ そ一 ︶ つュＯＣ¨ ■ 零 多ｃｏ ＾ ． 一 疑霧露 霊︶ 聾一 請一 柔菫 姜靖 十 一 や 卍 鶴 ぎ ﹁ 華一 一 ¨ 一 ¨ 一 ヂ詳雪一 ﹁ 〓“ ¨ 蔦費 ギ 暮 Ｉ多輩 ＾ ｏ ∽ コ ´ ． ′●■ つ ︶ ，■ ‘〓 ， ´ Ｆ¨ ´ ｘ， ︶ 〓こ３６ 〓 ，３ ゼ￠ 〓 ０〓Ｃ 一 ´′ 一“ ∽ イくプＧ一ｃヽ ´‘ ゴ 〓 ´ｃｃ 一３一 イ ■ ，一 ， ´〓一 ﹃ン ″一Ｃ ヽ ■ ，，〓 ｃｉ Ｃ﹃ ， コ● ア 一 一 ●●２ ７﹁コ●３， “〓 コｃｃ ，︼ Ｄ ■ ′〓ｃ，一 ３ そゴぉゴ 〓ＬＯ〓一 ｏコ ¨ 一 ３ヨ﹂ ｒｃ”ｃコ多 ”﹃ ´Ｃ一 Ｃａ つ”´ ０ ョ一 ●﹁ コ︵ 一 つ一一 ＣＣ一 ０戸ＸｃＯこ０コ ¨ “じ一 “一 〓 ２ ぞ０一 一 ０●３ ４ ，一 ε Ｏ●‘ 一 ｏ す一 一 ６′´ ヽ ｏ一 ＾ ン こヽε コ” 一 “す。﹁ ，ン，Ｃ﹁ ＞ａ ″ヨｏ■汀‘¨ヨｏュ﹂ 着ぢ ， ｃの３′ ♂ぞ０旨忍こ ， つ こく こぅ “ョびョン ︵ 〓〓３”一 二´ 宇＾ ¨ ′ ６ ０﹁多● ●“ 多 ｃ ｃ一●コ０ヨ 計 一 ヨ つ●■ ＾ ３ ′す計， ，︶一ズ●ヨ 一 ︶ ︺ヽ き ヽ 、 ヽ ヽ ヽＳ ミ ヽ ヽ 一 ｏ、 ミ ０ こ ヽ ・ ， ´ 力 ヽヽ ， ハヽヽ・ョ ミ 一 ￨: に 罐卜 ほ にに ヽ 虐ミ ヽ ■ に いぼ﹂ ■ ︱， 一 ︱ 霙 霙 輩 毛 表 聾Ｉ ︵ 奨 菱 こ に 〓喘 勇薫 一 曇姿 残裏拒尋一 三聖﹂ ﹂ 中 ， ´ コ ・ ´ 聾勇﹂ 露¨ 鍔一 聾´ 震靖夢ａ 華誓一 ヽ 一Ｉ墾一 ． 霧ジ勇一 声三 碑肇要響 霊毒¨ 聾序 葬 ﹁ ¨ 詐¨ 考 男 一 勇 委 ≒弄詳 尋 垂種 霜笙 ﹄ 一 ダ ． 弩叫 討´ 饗〓 ゴ¨ 夢﹂ 一 講威議毛誨 一 一 憂裁 諄 一 ・ ． ﹁ ． 靖 ５羮翌汗︺ ﹁ 誇託〆電一 一 桑証一 手 弱一 一 一 巽海メ ≒ 礎一馨 聾■Ｉ革つ ■鐸男 疇鮮許≒． ヨ■一 。 ， Ｃ ＯＣ¨ ´ 癸∼ Ｅ ﹁ ３´ ョ二 一 ４ ５ ５ ， ュ Ｆ ● ｇ う¨ ８¨ 〓 ‘ Ｓ 〓 ■ ´ ●３ ， 一 彎 ニ ユ一 ふ ¨ 一ｔ ま り 一 一 ︶ ， Ｆヽ ゃ ヽ ヽ １ 一〓 ¨ ＾ 賛こ ま 一 ＾ ３２ 一 ≧ Ｓ ュ や ， ヽ 一 ゴ 一 な ， ニ ヽ Ｌ 一 １ ， ′ 一 ， ヽ ¨ ・ 一 スタ 〓 ヨ ■ 一 〓 ´， つ 〓 マ３ ，， 上 う︸にユ 一一，ユ 一 一■ 一﹁ レ ご 〓 〓 ， く ﹁Ｊ ョ〓 こ ＾百 負 ェ 一´ 〓 Ｒ ， ｃ ＾ ｃ一 コ ｒＬ ● オ ー 一 ヴ﹁ ｔＦ ａ Ｆ′ 一 一Ｃヽ´ ＯｒＸ︶ ０ ﹀︶４ｃョ 一 ３¨ ０ 一 ム プｎ 一 ，一 ″ 一 コ一 Ｃｉ 、 ´´ ３ ＾ ´ ´ つ ョ ●，´ 〓 ■ ， コ ３ヽ ﹂ ７５ ズ ヨ 一 ＾ ５ 〓 一■ Ｌ﹁〓 ” つヽ 〓 ｏｃｃ■ ′ 一■´ ﹁ つ〓 す に ‘ Ｐ ´ ﹁一 ﹂一”・ 一・●＾ こ ∽ｋ´● ３ 一一口′︶， う´ ， ｏ﹁三０ こ ■● 〓 ニ ヨ ●ユ 〓 〓´ α 〓り，′コ ■﹃″”″● ３ ，¨ ４た コ・２ 〓●つｔ予 ｃ﹁， ｃ ， Ｆ ぉ ■〓 ”， ´ ︶ ∽ｃａ ｒｏ ， Ｆく ■ ■●こ ‘〓 〓 ´ す ， ｃ〓 ， ■●●一 一 ■ つ一●¨ 一 と ，κ一 チ Ｆヨ つ，ｃう一 ■＾ ａ ＦＬ″れヨ Ｆ セ 〓 ｒ ・＾ ●Ｑ ｒｉ ｔ ｃ〓 ¨● ■ ， ´ ´ イ＾ ‘ ¨ン ｒｒ ¨ ︶ ´ ︶ Ｐ ェ＾ 一 Ｐ ︵＞ ●０ ＾ １ ，ご ， ， ユ全 ， ´ πａ一 一〓 ｎ ｔ ヨ 一，＾ ，一 手﹁ ■４●６さ お４〓工”′． マ ε ， す一一， ‘■ ● 一 ５ ■ ■ ● ´ ，● ｏ﹁ ｏ■ ′ ‘ヽ ５ ｒゴヨ ●ヨ〆一 ■´ 一∞● ７うκ 〓κ ■ 〓く 〓 一 ヨ一 ａ ‘ ｚン ” ヨｃｎ一 ｏ〓 コＬ● ■，， 工う‘ すれつ〓 〓 ′０ ィ一 すｏつ■ 一 ア ” ４一 ´ 一ｃ′ ．薬 ´ ︶ ． ≒ ¨ 講﹁ ”狂 締理 一跨輩 誕董〓一 一 亜調三 工 露一 ■一 繁装ン 巽一一 一 望﹂ わ 装” 昇勇調一請 襲 葬一 ＾ 一 ％ 輩 鉾 ボ 喝 耗 拓 一 一 一 噴 ● ｘ・ヽｏ ２ｉｌ■８ ，ミｉヌ Э 葬響疑雲折 ・ 絹葬華響 調響釜輩一 塁一 ↓ 勢鰤一 一 殉¨ 菱 一 ¨ ﹄¨ Ｆ ”議繕車一 ¨ 一 ↓一 聾桑が一 一鵞罵 鷺 ︶ 一 翼黎 歳＝¨ 事告郷 乖 一 む 議 事隷霧 婆 轟字¨ 続 一 甕・一 一 一 一 執 権禦嘉癬 ・ ″ 髭﹁一 ． ´ｏ﹁コＣ“笙 つ“ ´ｙ〓´ 一ヽＣ 一 ゴ 一ＣИニ コ“ 一● Ю一ＣくＣコニつョ ＾ＪＣ¨Ｃγて 一 一一 ，コ´ ３ ｇ﹂ と ´う ■ 一 〓 〓 〓 ■●■ ヽ ３ ３ 〓重 一 ，， Ｃ〓 一 〓 Ｉ 〓う 一 ” ひ 一 〓ヽぁ一 ゴ一 “¨´一 Ｆｃ，２ｃ 〓ヽメｘ ●″ ｒへヽ一ヽ ■ｃ●ヨｃヨ ， 一 ｏこ ■ ８Ｆ， ， ＣヨｃＦそ一ｒＺ，ｏ‘ ”ス５´ 一 市〓 くぉ´〓 ´〓〓ｒ■ｏ一 ■ ， 一 ヽ トミ 一 つコ ● 一 ︵〓 〓 一 一０ デ 営 ‘ 一Ｉ ｃ一 ■ ヽ こ 一● ■ ぉ 一 112 ち 掟 ご羊ミ￡︶ｔ ａささｔ﹁ ミ、 ・ にに ざミミ、 ｔ ﹂ミＬほにイド〓﹂ 一 に﹂ ︲ ， ︲ 降燿■・ ￨ ︺“” ぃ カノ/71″ ″“″α “″わわ″■ ざOl_DO″ り '′た '2″ _二 ユ Jユ ″″″・″:″安 ′ ゴ ノィ177J″げ ″ι ___ crcy rnd strfctr of plutc14rsrrcorcdwith r Fhotilchcnricolp(rccrs [or prthogen inrctivatioor thc SPRIN:l tri!1. Arrxl. ]0{).1:lt)Jl lj:lJ-l5Jl .iJ. P(rpovsk\'NlA. (lhrplin HC Jr. lvl(nre Sts. liansfusion-relnrcd n(ut! lurg injufr: a ncglccted.scilrus cofipliciltion of hemothcr, lpy. TftnttliLtk'n. I 991:3:riti9-59:. .l-i. Jlchson BR. Busch MP. SLramcrSL. AuBuchcrnlP Thc co\F cffcclivcncssrrf NA-I for HI\'. tlCV and HB\r in rvholc-hlor)d . donalionr I runsJitsiot.2t)lj-lltl:7?l'729. -i6. Pillonel l. Laoerche S. Si\ura C. Dcssnclo\ JC. (:o!r{Ncr AM. rir!l infeclionsin Trendsin residualrisk of lransfusioo{ransmi!r0d Frnncs btt$een 1992rnd 2d$. ?'zn.ri6dr. 2lI)J:J:i98tl98s. -11. Yey JNl.Bottcmd{ lvl.Pr;hos C. Postmalv{.Staginnus ti. Eronom. ' ics o[ transfusion.,lxlus Ther Tntnslut Med.:{l)i::q::ls-225 -i8. Vun Hulst i\-'1. de Wblf J. Strginnur t.t, Ruitanbcre EJ. l'osrm! iUJ. Phtrmagoelosorricr of b[Dd lrnnsluliDn scfclv) reriew ol lh( ayaihblc €vid.ncc. f./J.Sra(. :(r)::$}IJ6-IiJ. .lr, CrnssJA, Hei DJ. ludtchrile K. ct il|. In.criv!tion of letkocytcs in llilrlel cr)nrcntrnlesh:- psorrlen plur tiVA. Srrrl l$)$:911 :tr{0.ltf{*. Jl). KnuL\ooF..\Jlunt(' R, Dupuis K. ct Jl Ph.ilouhcmicrlinrctivrtion rrf brctcrir rnJ tllV In buftt.(ort-duri!cd flilt(lct conccntrxrc\ undercr)nditionslh!t prusravcin vilio plal<letfuoction.1,1,.( Sdr.{. :lII):7rt::tJC-: I 6. .ll. l-in l'..Crn)k DN.Wicschahn (lP.r tl. Philochcmicil in.crivrti(rt of virusesand b0cleria in platclcl conentrites h! usa oi a nolcl p\,)rrlrtr rnd h)ng.w,r!ulcnelhultriri,rlcr lilht. filnr,fit.\iln'.1991. :.;:l:l'J.ii. l:. Lin L. Ditunrao R. Molrnr B. ur il PhL'tr)chumiirlrcilnrunr ill phiclet concrntrttcr wirh omrnosnlatr x0d Ionr-waiclengthultrrr viol.l light inrctisrres c brrad spcctrun ol prlhogenic brcrcrii. f,n,!li.\r :Ur)l:{.10(r. jr )J "t. {.1. Kimura H. Cost ol HIV treirnrent in hiehly rctive antirelroviril rh.rnpv i;Ynpan lin JJprnesej./v{,pun /lirrr,r :i,l}?Jil:il3-sl6 u. lshidil Il. InDuc Y. wbng JB. Olih K: CoJt efFcrtivcness o, rih' !ririo Flss inrcrfaron nlpha-2b for airhcr inicrleron relxpscsor non rusporJcrs in chronic heprlilis C': a Jrprnr,!! lr;al. lli:poktl /ldr :ln4:lsrl:J-1i6. ′ 772中∫ ο ″ν′ ″ ″読421111S,1,3'9-387 doirl0.lll 1r,1365.3148,2005.00609.x ORIGINAL ARTICLE C6St=effeOtivenCSS pfpathogen inaCtiVatiOn for plitelet transfusiois in the Netherlands ´ 露瘍脇淑器:挽 驚 穏材脇患 ]揚 蹴〕 脇 糧お源乳淵務蹴=朧 、 ル″“ Ica′ C aFrre Cra″ ■.C“●R甲 ,r/1′ Ⅳ′ i撃 2"ι二S./br′ "らclὰ●/11C・ ′g″′ Mα:″0,3SA,α"′qB∝ セr,M崚 ″ S″麟 電● “″1赫 § R′ ὰノ"の ′″￨`lρ́′ル′′め′ ″"″ `力 ““ セαあ″′/′″′200, suMMARy. The objcctive of this study is to estimate cost-effectiveness.ofpathogen inactivation for platelet transfusions in the Neiherlands. We used decision tree analysis to evaluate the cost-effectiveness of the addition of pal,hogen inactivation of pooled platelers to standard procedu{es for platelet transfusion safety (such as, donor r€cruitment and scredning), Data on transfusions were derived from the University Medical Centre. Groning€n (the Netherlands) for 1997. Characteristicsof platelet recipients (patient group, age, gender and survival) and data/assumptions on viral and bacErial risks were linked to direct and indirect costs/benefitsof pathogen inactivation. Post-transfusion survival was simulated. with a Markov.model. Standard methods for cost-effectivenss were usedl C0st-effectivenesswas expressed in n€t costs per life-year gained (LYG) and estimated in baseline-and sensitivity analysis. Sensitivity was analysed with rcspe{.t to various assumptions including s€psis risk; reduction of the discard rate and discounting. Stochastip analysis to derive 90% simulation intervals(SIs) was performed on sepsisrisk. Net coslsper LYG for pathogeninaqtivation w€reestimated €554000 in the baselinelweighted average .thre€ palient groups (90% over the SI: €354 0001092500). Sensitivityanalysisrwealed rhar cosreffeativeness wasinsensitiveto viral risksand indirbct costing,but.hiEhly sensitiveto the assumedexdess transfusions. required and discounting of LYG. Given relativelyhigh net cost$ per LYG that are intemationallyacceptedfor blood trausfusionsafety interventions.our estimatedcost-effectiveness figures for pathogbninactivition may reflectacceptable costeifectiveness in this specificarea,Two.tuain?r$umptionsofour m<jdelwerethat the pathogeninactivation was 100%€ffeativein pr€ventingtransmission of the patlogensconsideredand was not associatedwith major and/or costly adverse reactions.Validation of severalciucialparametersis required,in particulai theDutchriskfor acquiringanddyingof transfusionrelatedsepsis. In the Netherlands, safety of.transfusion of blood and blood products is largely determined by supply of available technology. The.major goal of public health authorities in this field has been to achieve maximum transfusion saiety, For example, newer and beiter tests for blood-borneinf€ctiousdiseases are.rapidly iirtroducedin screningproceiluresfor blood donors,such as nucleicacid amplificationtesting(NAT) for the human immunodeficiency virus (HIVJ. Next to the 'maximum-safety'criterion..cost-effectivencs is becomingan importantissuein judging new technologies,alsoin blood transfusion.Relativelyhigh costeffectiveness ratiosareseeminglyaccepted in ihe blood transfusiongrea (Van Hulst el al., 2002;Yeh el a/., 2002).For example,at.estimat€dcurrentDutch levels ofrisk for HIV transmission throughtransfusion, Hry NAT iosts severalmillibnsper lifc-ye:irgained(LYG) (Postmaa al., 2001).This fnding is in line with Correspondene: Dr Maatto J. Posrma. Associate Ptofessor in Phamacoeonomic, Universitylnstitrtefor Drug Groningen Exploration/Uniw$ity ReearchItrtitut6 of 9f Groningeo Phamacy,ArtoniusDeuinglaanl, Groningcn9?t3 AV, lhe Netherlands. Tel.r+3f 50 3612607;tu: +31 50 3632772: e.hail:[email protected] @'2005Blackwell Publishing Ltd Keywords:cost-effectiveness, pathogeninactivation. pharmacoeconomics, platelets. 計 ｍＨ． thnslusion durin! nn epid(nric in Quccnr, Ncw York C_irv. 7iur. fxrr(,r. ;lI)::J:. I tl | 9. I l]:6. ! |. DrdLl R. Leiltl D. Emcrginginfcctiousthrctls td thc bl(Dd supFt\. ianlr 8r! :Vrtt:({).r:si l9l.:07. ll. lvlilrsul'!tilshiK. Nasroka Y.Srkrra lJ. cr rl Trinsfusion.lr)nrdirrcd hcpatrtrsE cruscd hv !fpilruntlr rnJie(nuushcpilrrlr!E rirus srrarn in Hrtkkairlo. Jlprn. ftmrlrar,', :0(N;+ll)ll.gd). Z--r.Busch !,P Klcionran SH. Ncnk) GJ. C!rrenl and ctr)crgingiDfcctious risl5 r)f b||r)d transfusir)ns..rl,Ull' :(ltl.li:lJ9:959-96:. :4. Scihiz! YK. Purcell RH. Vrshikurr H. Correlarirrnhctween rhe infcqtivit\ of heparirisC virus in !r!r) rnd its infccti\itv in !,rro. Pnt ltit| Acu| Sti L/,1/. Ir)i)-lJ0:d)i7-60f,L f.5- Saz,rntaK. Rafrorti of j-is trrnrfusirh.asvNiillcJ dcurhs: 1976 . throu!h ll)85- fuilTltLri..rl l9t)o;i{)r.5ti.l.5q). :6. Bcck{rs e'\M. tcBekhorst PA\\1VcrnrLijH. vrnRhrnso DJ Linr. itntions of routire brcterial scrccninBo( pldrelctswith (hc Buc. -Iilcrl sy\rcm-Vhi sirr& :n)f:N7{runll -r):6-7 H. Lr)8,chen VandckerchrrvcB. et rl. Four.rcrr erpcritncc !7. Cl;rey-s wirh ioutinc hqcleaialacrdening(jf pln(clcl conccntrntrs.In: Pro. ac&lutqr o_ftht'l/lll Eunrytn C,,n!ft:r: ol th. lnn'rnuxnnl .Su'i. ert o l Bluul Trunfutiun, !:runhul. l?.(r-!. ,//) ,l.r), 100J. '^ fi ! t crd{m.The Nelhcrlnn(1.:lntcrnrtionrl Sr{(:r) r!{ Bk)rrd'lii}r\fs\ir!F: :rXl,1:5(i.. lb. Hrnna tl.\. Ruild L Bbod products:r sieililicanlrisk ttci(v l$ l$tr!,-tc(nr ctlhetecrcltlrd bhxrdstrtrm in(rtiion-\ in citrr!'r pittichtr. | ilftrt C(,ntml I losp Iipilonirtl. !'{x)lill: 165-l(fi. :9r Klutcr l{. ChapuisB..Ctzenn!eJl'.er rl. Aphererir pintclctstrdrrcd ' with lhc Inlcrctpt Blo(XlSt\lcin htr pillhrlen inrdi!aair:n provirjc Plnlclcl irun! incremcntslnrl h..nrgsrrsisconrpartblc to cunrci. ti('nrl nlrtclcts. I'r,r Jdn( ltXl:.Si(suppl :t:l llr. j0. Ossllrlr JC. Do)rt (:. Sr)nel.\. cr nl. Rourine uic i'f flireler drxil. p u r r c n t s t ' t e P a r c d w i l l t l ' l r o t o c l r c t r r i c rtlr c i i l t l r u r r {t l r r t c r c c l ) l plateht-()iimlncl on clinicrl r,utconlestnd{ost3. Blrrl lo pr€\s ll. Jopu (irnrtrl Prolih: lleuhh ( tn, E.rpuilitntc hy Sutu.Princa- t ton. NJ: F.sDiconr: llxll: lj. il. Fcldmrn EA. Bnyer R. ltl,r{/ l?nlt ttlDS. Dlu.nl, util rtu lbluits tl .lfLrltcal Distt:u'r. Ncu Y,rrli: C)xford Unircr:il) Prcssl l{ 9'). ,ij. fvlccullou-(hJ, Vcsolc Dl'1. Brnjamin llJ. cl rl. Tlcrapeutic rffi. ___二 Cosr-effecttvensssof pathogen ihacilvation in platelets 380 M. J. Postmaet al. e Elimination of risk for parasitesand viral infections, suchas HIV, HCV and HBV. r Elimination of risk lor sepsisdue to bacterial infection. r Blood bank processing benefits,suchas improved discardrate ofplateletsdue to prolongedshelfJife potential and eliminationof gammairradiation. o Elimination of risks for yet unknown emerging . pathogens. r PoFntial reduclionsin judicial claims following fatal transfusion-transmitted infections. Cardiology 410/o MATERIALS Risks of pathogen tmission AND METHODS Given the existenceof thorough donor selectionand routine donation screening for HIV, HCV'and HBV, virally infected donations are very rare in the Netherlands. European estimates for the risk ofwindow period donations in 1997were one in 2.3 million for HIV, one in 620 000 far HCV and one in 400 000 for HB! (Miiller-Breitkreutz, 2000). In the model, we applied reedt estimates that ard considered specific to the Dutch situation at,one per 200 000 for HBV and one per nillion for HIV and HCV (Health Council, 2003). Transfusion-related sepsis is most often related to platelettransfusions.Approximately 80% of casesin the UK were estimated to be telated to platelets (SeriousHazaids of Transfusion (SHOT), 2001), An internationally published (Yomtovian et al., 1993; Ness et a/., 2001) risk of 0.04o/o per platelet transfusion was deployed in the model as upper bound and investigated in sensitivitj, analysis (see below), Corresponding cas€ fatality for sepsii was a$sumed at l5% (Nesset a/.,2001). For the lower bound (also invstigated in sensitivity analysis), 0.025% was taken for platelet transfusion-related sepsis with a related case fatality of lJ% (Morrow et al,, 199\; Saama, 1994). For the baseline, the intermediate risk at 0.0325% and intermediate case fatality at 160/owpte assumed, On top of these estimates, we assumed that the recently implemented bacterial screening only slightly reduces the sepsis risk by epproximately 5% (almost 409/0of positive units are General design We developed a pharmacoeconopic model tha! links chaiacteristicsof the population of platelet recipients (agt, gender and outcom€ in tems of survival) with economic aspects of pathogen inactivation. The pharmacoeconomic model.estimates cost-eflectiveness in tems of nct costs per discilunted LYG, with inclusion oi direct and indirect costs and benefits. Diiect medical costs relate to the costs ofpathogen inactiva: tion. Direct benefits are related to costs of treatment and care for transfusion-relatedviral and bacterial inlections and elimination of gamma irradiation. Indirect benehts are related to averted production lossesrelated to aierted deaths due to infections. Patienr popularion l 2005Blackwell Publishing Ltdr TtoNf6ionMedicihe,l5,l7F3E7 Paedialnc oncdogy 4% Haematology 43'/" Fig, l. Distribution of patients(upper) and tlansfusions (lower)overpatientgroupsin the UniversityMedical CcntreGroningen(data for 1997). Table l. Pqcentagcdistribution ofplatelet transfusionsfor threepatient groupsin the Uniyersity Medical centrc Grbningen in 1997by age and gender(r : 603 for cardiology,n = 120for haematologyand r : 30 for paediatriconcology) Cardiology Age group (years) く1 0 10■20 211 30 311 40 40-50 51160 60-70 7∈ 80 >80 Total Male (%) Haematology Female(%) Male(%) 13 05 08 05 02 13 96 123 2.3 28.2 ◎ 2005 BlackwdI Pubushing Ltd,ル a可 レs●"MCar′ ル,15,379-387 ７ ８ ８”邦”口回２ ｍ︲ ・５ ，０ ， ９ The phamacoeconomic model was developed for three separate typical patient groups, as costeffectiveness for blood transfusion safety interventions may strongly vary between such groups (Van Hulst el a/.,2002). For exarnple,application ofviral inactivated plasma was estimated to cost US$59 000 per quality-adjusted LYG in trauma patients and US$122 000 in cardiac surgery patients (AuBuchon & Birkmeyer, 1994), Applicaiion of single-donor platelets instead of pooled platelets was estimated to cost US$200 000 per quality'adjusted LYG in cardiac surgery and US$470 000 in haematology (Lopu..-Plaza et al,, 1999), In this srudy, we elaboiate cost-effectivenessfor three patien! groups giving rise to the major share of platelet transfusions in the Netherlands: cardiology, haematology and paediatric oncology. Transfusion data of patients were gathered in the University Medical Centre Groningen (UMCG, the Netherlands) in- 1997. Figure I shows the distributions in terms of patients (Fig. la) and transfusions (Fig. tb). As shown, cardiac surglry patients - primarily undergoing coronary artery bypass grafting - represented almost 4lyo of the patient population receiving platelets, whereas in terms of platelet transfusions their proportion is lower (23%). In terms of the number of transfusions, haematology accounts for the major share. Table I lists the distributions of plalelet transfusions over age ２ ０ ０ ■ ９ ３ 一 ９ ３ １ ︲ ︲ ︲ ２ ７ In the presentstudy, we assessthe cost-effective' nessof pathogeninactivationin platelets.The scope of this article is limited to elimination of risks for known bacterialand viral infectionsand imnrovementsin bloodbankproessingwith regardto elimination ofgammairradiation.Benefitswith r€spectto reduced discard rates may have already been achievedin the Netherlandswith the implementation of bacterial screeningin 2002. Benefitsof averted spreadof yet unknown emergingvirusesin platelets and inclusionofjudicial claimsare ieft for discussion and further work. Future applications of the INTERCEPT{ Systems,comprisingthe whole spectra of pathogens(including nonenvelopedvirdses) and products (including red cells and plasma), enhance formal consid6ration of such further benefits, inclusive'of potential omission of any of the usual tests on donor blood for viruses and bacteda on the long-term. Paediatric oncology Female(0/.) Male (%) Female (Vo) 467 20‐ 0 667 333 守酬Ｈ estimats of NAT for HIV and heparitisC virus (HCV) in other countries(Pereira.& Sanz, 2000; Loubidreel a/., 2001;AuBuchonet al,,2M2). Despite high levelsof safety achievedin Dutch blood transfusion, risks still remain. Relatively small residual risks have been estimatedfor HIV, HCV and hepatitis B . virus (HBV) (Miiller-.Breitkr€utz, 2000).Particularly,for plateletsrelevant risks of bacterialinfectionand subsequentsepsisare €stimated, with significant mortality rates being reported(Sazama,1994;Nesset aI,,.2001).Estimated sepsisrisk afler transfusionis highest for pooled platel€ts,with risks being suggestedup to one pet 2000units transfused(Sazana, 1994; Lopez-Plzza et al., 1999).In the Netherlands,pooled platelets refleat almost all utilization of platelet transfusions (Sanquin,2000). A new pathogen inactivation. technology-the INTERCEPT@ PlateletSystems-achieves reductions in pathogenloadsin plateletsbelow detectionlimits viruses- suchas HIV-I, for all relevantenveloped HIV-2, HBV and HCV - and many bactena- such as Staphylococci coli (Corash,2000). andEscherichia The INTERCEPTo PlateletSystems(furthei: pathogen inactivation) is based on psoralen treatment. Application of pathogen inactivation for platelets may achievebenefitsaccruingat variouslevels: 381 groups and gender. This distrjbution js the basis for our pharmacoeconomiq model below. . 382 M. J. Postma et al. not recalled,and over 90%.of recalled platelet units are already transfused) (Beckers er al., )-005). Excess morialities for HIV and HCV were set at 6 and l%o per annum, respectively (Loubid.re et al., 2001; Postina, Wiessing et dl., Z00t). Mortality due to HBV infection was neglected. Costing sspects 跡 Ｕ Ｗ 鼎 TBbl€2. Diregt cosrs for viral infectionsand bacterial sepsisin € (pria level 2003) used in the model (costsfor. humatr immunodeticimcy virus (HIV), hepatitis C virus (HCV) and heprrtitisB virus (HBV) are lifetime discounted costs) (Strujjs et al.,2000 Postma, Wiessinge/ ol., 2001; Van Gestelet a|.,2002;Postmaer a/., 2005) 83200 19500 1100 20600 The costs for pathogen inactivation were assumed at €116, the currently envisaged price for hospitals (including margins for required production process changes in the blood banks; personal communication with the manufacturer), Additional costs are Doi€d by pathogen inactivation that may potentiaily involve yield loss6s. We.assumed a l07o inoease in the costs per platelet transfusion unit to account foi this factor (McCultough et al.,2O0l; Van Rhenen et at.,2003). Additionally, in the trials performed for INTERCEPTo, exess transfusionswere required ro achieve adequate count increments. In the US SPRINT trial,.such exess transfusions were more than 30yol in the European euroSpRITE trial, no significant differcnce was found (McCullough er al., .2001;Van Rhenen €/ aL,2003), In our ahalysis,we assumed l5olo excess transfusions .wlth pathogen inactivation (0 and 30% in sensitiviry inatysis). Excess transfusions were monetarily valuated at the estimated cost price per platelet transfusion unit of €458 for adult and €285 fot paediatric application (Sanquin Blood Supply: price list as of I March 2003) plus €l l6 for bacterial inactivation. Finally, benefits of elimination of gamma irradiation were inserted in the model, assuming this elimination in l0oZ of transfusionsin haematology and paediatric oncology at €30 per irradiation. Phumacoeconomlc model The distribution of platelettransfusionsin the UMCG was the basis for our pharmacoeconomic modEl. This distribution was conceived to reflect the prbbabiljties that in individual unit is tiansfused to a patient of specificgender,ageand patienr.group. For eachpatient group, an age- and gender-specificMarkov model was developed for post-transfusion survival. Suruival results from death risks due to viral/bacterial infection through transfusion, post-cardiac surgery death risks and those due to other causes (natural mortality), Details on transfusion-related infections are listed be)ow; mortality for cardiac surgery, haematology and paediatric oncology patients was estimated at I 7, 38 and 31o/o,respctively, in the firsr year (data irom the UMCG for 1997) and t, 5 and 0.5yo, respecrively, in gubsequent years (The Bypass Angioplasty Revascularization Investigation (BARI) Investigators, 1996;Lopez-Plazaet a|..1999; Coeberghet aL,.2001). Natural mortality was taken from the national statistics (source: Dutch Central Buriau of Statistics. Voorburg, the Netherlands). For the three pdtient groups considered, a weighted avbrage for cost-effectivenesswas also calculated (proportions of. 'transfusions as weights; @2005SfackwellPublishing Ltd, TranfutionMedicine. tS. 379-38? Fig. l). As shown in Fig. I, th€ patient groups in our model are estimaled to consume 70% of Dutch platelet transfusions. Figure 2 shows above in the concept of a decision Cost-effectiveness was exprcsdd in net costsper LyG. Net costsrefl€t the costsof pathogen inacdvation minus its monetary benefits.Monetary benefitswere related to either the elimination of risks for viral and bacrerial infection or gamma irradiation. Monetary benefits and LYG were estlmaled by comparing two options in ihe model, In a fimt step,the financial cosrsand life-yearsIost were stimatrd in the absenceof pathogen inactivation with risks for'transfusion-related viral and bacterial iniections as sprcified above. In the next step, pathogen inacl.ivation was simulated, corrcponding with rero risks for infectioirsofpathogens consideredin tirjs analysis:In addition, elimination of gamma inadiation was assumed. Differences in costs and life-years in both options were comparcd subsequenlly. ' Cost-eflectivenesswas estimated in the baseline and sensitivity analysis. Deterministic sensitivity analysis was performed with respect to viral risks, bacterial risk, reduction in discard rate and discounling of LYG. For stochasticsensitiviiy analysis, Monte-Carlo simulation was peiformed with rspect to the annual number of tansfusion-related sepsis cases (poisson distribution) allowing calculation of 90o/" simulation intervals (SIs) for. cost-effectivmess. Microsoft Excel 97, @RISK 3.5 for Excel (Palisade, London, UK) and DATA 3'5 for Health Caro (Tree,Age Software, Williamstown, MA, USA) were used for computer implementation and presentatiotr. 3g3 €69 300 per l0 000 transfusions in cardiac surgery (10 000 also approximately reflects the annual number of Dutch platelet transfusions in cardiac surgery). Of th€se benefits, 96% referred to averted cases of sepsis (also for the other patient groups, sepsis accounts for the major share of benefits; however, additional benefits come in for elimination of gainma irradiation at approximately 30% of tolal benefits). Furthermore, per l0 000 transfusions in cardiac surgery, approximately 4.4 discounted lifeyears were gained and cosrs of €2169 200 were made, rendering net costs of €2099 900 and net costs per LYG ar e474 000 in the baseline(90% SI: €302 500-€940 300). Baselineestimareslor the orhe, patient groups - haematology and paediatric oncol. ogy - were €678 600 (90% SI: €434 000-€133S 300) afld e260 700 (90o/oSI: €t66 800-€51 I 200), respectively. The weighted average over the thlee patient groups was estimated ar €5S4 000 (90i" SI: €354 000-€1092 500) As nientioned, SIs formally represent potential annual fluctuations in cost_ effectiveness. Sensitivity analysis revdaled that our results are insensitiveto the exclusion of avertedviral infecrions and exacl levels of assuiled indirect costs (not shown). Model results were sensitiveto seosis risk and relared case fanlity. the assumed.*".is rrunr. fusions through inactivation and discounting .of LYG (Table 3 lists results for weighred average ov€r pattent groups). In percentage changes, resultr were most sensitive to higher excess transfusions assumed(r74% of baseline)and nondiscounting of LYG (-38Yo of baseline).. RESULTS DISCUSSION AND As an example,estimatedannual monetary benefits of pathogen inactivation in the baseline accrued to Cost-effectiveness of pathogen inactivation of platelet transfusionswas estimated at €554 000 p.. LyG in the baseline as an average ove! three major patient CONCLUSIONS Tabte3. Sensitivity analysisfor the cost.eff*tiveness ratio in net costs per life-year gained (LYG) (in €; prie level 2003)on sepSisrisk (and relatedcas fatality), exccsstrans" fusionsand discountrate for the weightedavcrageoverthe throe patieni groups considered(cardiology, haemarclogy and paediatriconcology) ° f LYGl山 Fig. 2, Decisiontreefoi the cost.effectiven$sa@lysisof pathogeninactjvatioq. @ 2005BlackreliPublishing|ud,Tra&I&ionMedieine,tS,3t9-38.1 ∵灘 翡 締 淵 No cxoOSS transfudons red req面 393 500 ExcOSs tran,Ⅲ iOns rCquired at 300/0 961500 Nondis∞vAlng or LYG 341 200 ｎ ︻Ｈ AII costsin our analysis were estimatedal price levels of 2003. If required, annual deflators of l.8ok for direct and 2% for indirect costs were used (Oostenbrink et a1,,2000), According ro rhe Dutch guidelines for pharmacoeconomic research, future costs (and LYG) were discounted at 4%oper annum (Riteco el al., 1999). , Lifetime, discounted direct costs for transfusionrelated viral infections were available from the oublished literature (Struijs et at.,2000; Postma, Wieisiirg et al., 2001: Postma er al., 2005). Direct costs for transfusion-related sepsis were based on a recent Dutch study (Van Gesrel et a1.,2002). Table 2 lists th€ cost eslimates as used in the model. To enableestimation of cost-effectiveness from the societal perspective, indirect costs were included for death due to any tr'ansfusion-related infection. i.e. HIV death, HCV death and sepsisdeath. The societil perspective is preferred in many international guidelines for pharmacoeconomic research, including the Dutch ones (Riteco et al., 1999; Hjelmgren et it., 2001). Indirect costs were estimatedusing the lriction coshng.approach, as request€d by the Dutch guidelines for pharmacoeconomic research fRiteco el a/.. 1999; Oostenbrink et a1,,2000). As opposed to the human capital approach, the friction costing approach only counts indirect cosrs of productioi Iossesduring a period of a limited number of months required to fill in the vacancy. The human capital approach calculat€s production losses during all future life-years that are lost due to prematur€ death. Cosl-effectiven:essof pathogen inactivation in platelex 〇３ ヽ 一 ‘ミ ヽ Ｒ せにヽ３ ● ミ、ヽヽふ ｏいヽヽ き ヽＲ せ ミ き ヽ き ヽき ヽ や ０ ぃ﹁ぃ い∞ヽ ヽ ミ ´ 卜 ヽｓｔ ミ ｏ ■ ●〓 ど ｏ一ざ ● ， こ ｏ︻ ＯＬくｏ， ｏ﹁ Ｏｏうｏ﹁お ｏ﹁ ｏ，一すｏ﹂ｏコ 一 ●，ｏ一 ︼● ｏＯ●゛¨ 一く〓︶ ”り，一 しいヽ ＯＯＯ ∽・ ， ﹃，●”ｏ ，一ＯＣ，０ ハ¨ ︶∽一 守 ｏヨ め い一︼ やｏｏ 一 ｏ め つい一 いｏｏ ‘ ”∽一 ●０お ，お ０︶げヽ ０∽∽‘ヨ ・ 一 ｏＸＯｏ一∽ ●¨ ●ｏ●０おｏｏＣ，ユコ” げンパ］ ，うＯ ωＯヾい 一 ”，●資ピ‘ 澪︶一 り一 ｏ●゛ ヽ‘ｏ 一 ●，ｏＬく”Ｌｏ●´﹃ｏ∽つ００ＬくＬ ヽ 〓ｏ ﹁，ヨ ｏモｏ一″゛ ｏ﹁ 資 ０一 ︻ す ¨ ● 一 ８ 臓 ヨ ｏ●´ ∂ ︻ 〓僣Ｆ く，ｏ●一 ｏすｏ︼ ｏ，´ ｏ﹁ｏ一ｏ●０ 一ｏくｏ”，一 ，”Ｌｏ● ｏ一 ‘０一 ｏ∽・ ０〓 ， ∪ ●一 ，︻， デ２ ０ δ ■ ，ｏ８ ﹁Ｓ 〓 ｏ ，■ ｏｏ∽， つｑ Ｏ一 一 ８ ｏ●●お ０ ｒく の ｏ﹁，もも﹁ ０こヨ 臓 ｏこ ０いｏ ｏｏｏ ゴ，∽ σ００● 一Ｃ””９ ぉ０ ”ｏ■●５ 〓 ｏこりｏ・ ミ ヽ、 いｏ⇔じ・∽●０一 一 ずヽ ヨｑ ︵ ｏ∽すｏこ ´０一 ・ ‘ ０９ ■ｏｏ● ｏｏｏ一 ざ ●∽︵ ○ ■ｏ口´ ■一 ９ ，コい ０９ ■ｏｏコ 〓 お ，ヽ ｏコ一 一つつ∞︶ ﹁ｏ一９ ”ヨ ■ ｐ ∂ ﹃一 ざ ● ３ ︻■ｏ９ ８ Ｓ ， ﹃，●一■ ●●Ｓ ¨ ・ Ｌくｏ一 〓” ０∽﹁ ０一〇Ｏｏ＾ ｏ一口ｏ一 ‘ ＯｎｄＯ﹂くｏ●ｏ∽∽，一０一 ５〇 ヽ ゴ一 ”ｒ 一 一〓・ ﹂望 ｏもも〓ｏ﹂ と 二一 デ一 すｏ一 一 〓０ ●一 ””●一一︼ ”●︵，一一 ０●∽ｏ﹁一 くｏ一，●﹂ 一 ︼ 住ヽ め ︼ｏｏ ｏｏｏ も０一２ ∽ ●●” ０００﹂●¨ ｏ一一”ｏ● ョ ，一 ０●ｒ●８０ ｒく の ︵ て一 ， ■ ヽ ヽＦ も ︶→ ＞ 一ミ ミ も 諄 ﹀ ，一 ８ ∂” ・ 一 言”一∽Ｐ ゛¨ く色 て ，一 ｏ● レ，お一 メ ﹃ε”＾ ”デ ●ｏ″ ｏ●∽， ｏＯ一 ２ ， 一 一 一 ｏＯ●●８０ いく０ １ ●ｏ 一 ｏ Ｏ●０ 日 一 ｏ● ０． ｏｌ 一 ｏｏヨ 一 ｏ げ０ ヽｏ●ｏ﹁一 〓０ ” ４０” ”ｏ﹃ 一 ｒｏ﹁ ００●●一 〇０ 一 ヨ 一 ，●﹄∽ ，●一 ０一 ︻一 ｏ 一 ヽ ゃｏ一一 ︵ Ｂ Ｐ ∽Ｓ ”ヨ コ●ｏ ミ ﹁Ｆ いｏｏ︼一 く，● 〓 二 ， ヽヽ ミ ‘ や〇〇ゆ一く 鮎¨ ミ ヽＦ いｏｏじ ﹁ｏ一 ｏｘ，日 ■ ９ ■０ ８ ８ ●一 ぞ ＞↓ ｏ﹁Ｕ ｃ一 ０´﹂ヨ ，お い ００βお 黎０９ イ●●ｏ′ ｏ﹁ブ一 ｏ” ヽｏ口ｏ， ∂ ︻〓 ︼＜ 営 めＮｏｏ ８ ｏ ６ ｏ６ 一０●０ヨ 一 ヨ ｏ● ６． ｏつ ｏ３ ３， 〓 ∽ ｏ■ ｏｏ８ 一 一 ミ ヽ■ Ｎｏｏや︶ ﹁ざ 日 一 く， ０日 ｏ∽ニロ ，お０ ぎ” ａＳま， 〓静＆く ８∽ ｏ 口 ｏ ， お‘ ・ ９ ８﹁零い ９ ま， ０っｏｏ一，９８〇一 一げぼ ぅ０一ｏｏ゛一 一 ョ，К ” ｏ０〇一Ｆｋバ︸ 〇 ‘” ，●２Ｖ オ ●ユヨ ”︻一 〓 オ ︼０す ” ぞ ∂ ｏ●８ ﹂ ｏ● ８ ∽ ０一 ＯｏＣ，お ０ 一お ︲ ヨ ” α﹁ ｏ ヽｏ，， ︵ ”ユ ●ｏＯ﹀ Ｚ ｏ●２ ∽●ｏ●５一 〓∽＾∽ ∂ ﹁ σ●ｏ一 一 ， ， ｏｏ●︲ ｏＬＬ 一 ●お ｏ一 ０い一 ”﹃ｏ 一 ● 〓つｏ そ 一 ，一 ｑ る ●一一゛ｏ﹁ｏ， ユ ｏ， ， 臓 そ 以 ｏｘ０８ ′ ００ ３ ，● ｏｏｏ● ︼ ︼ ８ 一一 ０● Ｏｏヨ ロ ●●一 ぞ ３ ８ ３ ｑ ヽ ｏす 一ｏ ， ｏ 口 ｏ∝ｏ Ｏ 。一 ＯＯＯｐ︶ ・ ︼ ︶●二●¨一 〓ｏｏ●●﹂‘０﹂ｏ，ｏ﹁ｏＣ︻﹃ ０す・げ，０おユ，一一 望Ｔ ０ ０∽ ０，︻ ´ 一 輩請弓 当灘輩り 鶉﹂ 一吹 撮 ¨ 講。 ０ ８ ¨●●ｏ● ↓ｏなｏ一 ″● ”く いｏメ一 Ｌ・ すｏ﹁す０﹂０ ィｏ一 月ｒｏ ］ ・ ”，０お﹃苺一お ‘ヨ ” すい一﹃ｏα﹂ｏ０〇 一 すｏ■一 ざ ５， パ ∂ ﹃■，●∽Ｐ ∽ ∽ 一 Ｌ すつ ざ う す 手 ｏＺ 含 〓ｑ す ●０， ”８ ０●一 ８ ご お０ げ，ｏお ” ８¨ Ｆ″ ﹁ ゴｐ一一 一 ３ κ゛︻ ｏＦ ゴ０■つくｏＦ す ｏおヽお∽一 ｏ。‘ｏ一 ｏ●３ ●ヽσ０ 〓ヨ一 一 す０ ６ ｏ﹂０● ０●﹂一〇〇 ０●一 〇０・ ０ヨ﹂ｏ●０〇 一 ● 一 く 一 ●∽ ●一 ． プハｐ一 すｏＯＬ ヽ ″︼ ｏ ”う０ ア︹ｏ︵ ｏ■，︼ ∽Ｏ︶り ０﹁一０﹃一 ｏ●∽一 ●つｏ ｏＬｏ一 ざ ∽，ｏｏ＾ ヽ■ｏ ３ ■，●∽ Ｐ ∽ざ ● ｏ﹃ 〇０∪ ＯｏＯｏ っいマ ” ″ｏ一一 一 一 ３ 一∽ど ∽ ｏ●８ ●３ ３ ●Ｚ Ｏ∽． ｙ ，ｏ８ ０●８ δ ●ま 魯 ｏ，●●●摯 夕ｏ∽一一 一一 ●●Ｂ ∝ｏ一 ，∽︶∽ 一 ｏ” ｏ●一Ｏｏ ，¨ ０∝● 一 ● ， ｏ 口，二ｏ５，一 ”︻一 ８ Ｌ一■，﹂ｏ● 一■ ● ︵ ヨ ，●一 Ｃ ■ｏＯ一Ｃ Ｕ ●”Ｆ ¨ 一つい∞﹁ Ｎｏｏｒ ，０づ一ｏメ一 ｏ﹃ ｏ﹂降ｏ︻ ｏＯ ，●●●２ ぞ ■５，ュヽ ｐｏＯ，∽０一そ０﹂ ， →， ６● ８ ＦＳ澤ヽ ぶＳ︶姜訂﹃ Ｓ∽８８ ，ａ ヽ ８ｏ ８ ， ０■ ， いｏ一じ 一 Ｐ Ｓ Ｉ ヽ 口 Ｓ Ｘ ”〓ヨ ，ユ エ Ｓ 一 ■ ｃげ３ ２ ｏ ，，一一 テｏ８ ０，い 〓０ ∂ Ｈ 一 ， 一ｏ ｏ●■８ 一一 こ ●０一∽ “●●●コ ︵ ヨユ 一 ●２●∽一 ｏ● ｏ﹁” ヨ ｏ﹃ｏも︻０ロニうｏ●”﹃一 ０一●ｏＬｏ● ０︼ｃ 一 ∽澪 ﹃ ｏ σヽ０一 口”● 一 す０●●﹃ ０■や一∽ ０■Ｏｏ●一 ●¨ 一 ﹃ｏ●一、゛い０● ●●”σ●璧Ｖ 一颯 ８ ワ 一 リニ∽な ０﹁９ ｏい０９ぷ 一 ， ０● ヨ ”ヽ げｏ コ ミ 〓 ｏヽ けｏ●ｏい， ｏ﹁﹁”一 〓ｏ”ｏ● ま ，８ ど ，口 こ ｏ■。 さ 一 汀 ８ ８ 一﹃ 詰 ‘ Ｅ ∽Ｒ ９ ８ Ｒ ヽ Ｒ ■ ｏ， ｏ一 ”一 ３ ３ ， ■ Ｓ Ｏ ， ８ 品 ， ■ ，■ ■ ，営 各 ﹄ ‘”¨ ∽¨ ８ 日ミ 簿 ”くｑ お ， 日すｏ こ 資ｏユｏ ｏｘ，３ ■ ｏ ｏ”一 営 ｏ一 ３ ●∽Ｐ ゛ざ ７ 社 一 訂 Ｚ ｏ， ｏ﹃一 コマ す 一 彗 針 ヨ ミ る ， ０， 日 ■ ●１ 主 ｇ ゲ一 ０一一 一 ﹁ｏ﹃﹁﹃ 一 く一 ■ ●●‘キ●●●一 ，一 くｏ ●﹂くｏ∽ ０ ” 〇 ∽´ ，， ｏ ０ ●０ ０ ヽｏ いく ０ 一ｏα●８ ｏ●３ ８ ∽お Ｏｑ ｒく ０ ●一 ８ ，一 日 ０資 ３δ ‘ ”︻一 一 一 〓ｏ い３一∽ Кｏ﹂″ ｏ﹁一 〓ｏ ∪ ●８ ｒ 工 ︼ ＜ ヨ ，”一 ●” 一 メ ヽ■一 一 く 〓 静 ｏ一 ｏ〓 日ヽ︶ ８ ａ 一ヨ ● ●一一８ 狂 ■ ，お ぞ ﹁ぶ ェ ︼ 〓●６ げ８ ● ２ ﹃ 一 ｏヨ ぞ ０●丼 ＆ ０望 ■ ●■ ８ ，”， ど ∽ ８一 一すｏ Ｏ●０ 一 α一 ●くロス一 〇０ テｏ一０・ 夕ｏｏ﹂，Ｌ●” ｏ﹁ ■”穴］ 一 一 ”，一 ０﹁●〓Ｌ で 会ｇＯ αｏ Ｏｏ■ ´いｏｏこ ・＞ くｏあざ ヨ ｏ﹁ ｏｃＯず ヽ● 資 ∽ ︵０ ２ ０ ∽●ｇ ｏ■ 一ｏ らｏＯ，お ｏ３ ｏ●” ０デ営 ■ ５ ｏｏ●００，０日 一 〇０ロニｏ ダヽ ０ 一﹃●●∽一 ｏ一一 ｏ“一 ｏ 一 ●一〇 ０一 ”０〇一 げｏ●ｏ﹁お ｏ﹁ ，¨ ミ ヽ Ｌ 毬 ｅｔ ａ ｇ ｏ ヨ α ，置 〓 ８ ８ ■ ︰ ● ８ ８ １ ● い０■ ●”一 ずｏ¨ｏ● 一 ｏ一 ［ン﹁い一 ●，０﹂く，Ｌｏ●´ ００﹃ ●ｏ●０ォ００●●一 一● ６ り全 Ｎ８ ０ ， ミ ミ い０３ ﹀ 。 をくｏ ●う，一 ∽″ いｏ﹃ 一”，●ＯＰあ 一 ｏ●︲”ｏ一 ，お ０ ∽０﹁Ｌ ｏ ヽ∽ｏＯ 一す０ ﹁¨ ∝﹄ Φ・ Ｏい一 ¨Ｏ Ｏ・ Ｏヽ゛︵ 一０﹁ ｏでｏ■ ， ﹁一 ヽ●∽一 ｏ ﹁ｏ●¨ｏ ﹁■９■¨ Ｏ 一すお一 Ｐ８， ｒｏそｑ ﹃ ″゛ す●くｏ 一 一 ﹃ｏ２ｏ ■ ・■一 ■，●一 げｏＱ● ３ 一０﹁８， ３ 一 ｏｘヽ日 ■ Ｏ Ｉ 一 〓０ ∞＞ ０日〓 ”て 一、ｏα “，Ｏｏ● ∽ご ， つ ︵ パ ●ｏす●ｏ■ ヽヽ ミ Ｎｏｏｒ ”ｑ ｏＮ ミ ヽｉ ‘ ゅｏ含 ︶ 弓すｏ ●■ げｏａ ｏ﹁ 諄 ｏ ♂ ﹃増 ｑ Ｒｃヽ︼ ｏｏヨ ヨ ■ ¨ 一 ｏに 一” ｒｏ一 Ｏｏ●ｏｏ■，界レ ｏ﹁〓っｃ︲ ０﹁一 ゴ﹃０●一 一 ｏ● 一 ﹂﹁う０一 ●”∽ｏ● 一 ●０一 ，ｏＯｏ ﹁﹃０げ、げ﹄ げ，ｏ一 ・２一●一 〓”一 ¨ ｏ■，一 ヽ●﹂●ヽ﹂ｏ●ｏ 一 ● ヽ ヽ■ ● ●０ ０﹃ｏ∽﹂ ●一ｏお ０ ヽ″ ｏ 一ｏ ｃ ， α Ｏ一■Ｏｏ ｏ ﹁Ｌ ｏ ” ”口０ ０く０一ＯｏＬ ・ すｏ ﹂ｏうｏ●Ｌけヽ一 一 庁ｏ ｏヽ︼ ヨ ｏ﹂０う ０﹁ 一 ０﹁ ｂ 一 ｏＣ一 ■● ︵∽ 一 ｇｏ﹂ ”ｑｏＮ ミ ヽ■ ●●ヨ σｑ ∽ 〓βＯ，Ｏ ｏ﹁ ■一●∽Ｐ ８ い ０■，︶ ︵ く ，８ 一 ■● 〓ｅａ８ ８，ｏ 摯一 ＾ ヽ６﹃ ０ 一 〓神一ヨｏ 〓︼ ヨｏ Ｃ″バ︺ うｏ﹃ げｏ一ゴ 一 ”い０ 一 ●ＯｏＸ ｏ●一０∽ ，う０ 一づ０︼∽０， Ｏ ｃ吋 ｏ﹂ヽ﹃ｏ●一”，０一 やヽ〓ｏＯ 一 げＯ Ｚ ｏ一 デｏ■，●ヽ， ０一 ｏ 一 ヽＬｏ 一 ∪３ ｏ 手 ８ ８ 妥一 ８■´● ﹃ ｏ ８ ， ５ 訂 ０一 ■ Ｓ ョ一 ３ 一〓 澪 ” ， い 一 ０ヽく一 ﹃ ”一ヽ●α げ”ｏ，Ψ ︻ ●︼一 ”う ｏ ｏ﹂ｏ●一 一Ｏｏ∽一ヽェ０３ ●●０ ︵ ，メ〓‘ 一 ２一 ●ｏ 一〇３ ■Ｆ ８ ８ョこ 〓 ・ ● ｏ ●ョ ヽ〓 ａ， 潔 増一 き●ヽ もぎヨ ８８８８ュ０ヨ８諄 ︵ ‘黎ｏ” ｒ饉´ 魯ヨこミヽ・ も３¨ ∽ い ュｏ ０ ２︶≧８・ Ｏげ ●， ●巴匡ｏ ｏ ３下 ざ ０ ， ュ ０﹁り ヽ﹁０ 一 一 ヨ ｑ げ８ モ●０● ｏ諄 ヽオな ︶ ０一 ●”８ 一 ”‘﹃０もｏ●● Ｃ ユ ｏ● ︵ ”Ｃ ︶ ｏｏ●●一 ■９ ﹁０■ ｏメ●ヨ ■ や そ０ ●０８ 手 ミ 静 ｏ ﹂ ヽ 日∽ひ ∽ざ 〒 ａ Ｓ Ｓ Ｏ エ ンヽ ｏ， Ｏｏヨ お ョ ョ ｏ Ｚ Ｏ一〓ｑ Ｆ 口００ 〓ｐ一 げ８ ● 〓ヨ 一 お Ｏ ｏｏヨ ●■ ０﹂ δ ”８ ， コＰ ０手 ０﹁ いＣ ｏｏ●●ユ ｏ∽ ︵ テ■ 一 〓 ︼０つｅ ●す０ ， ｏ ｃ ∽ ＞ いＯＯ ︼︶ 、 ﹁〓ｏ 一”︹¨ｏ﹁ ０一Ｃ ﹂ ︶ げ●∽ げｏＯ● ヽ﹁”ＬＯ﹂ ”０ アヽくｏ 一 Ｏｏコ ・ すｏ も，多 ｏ¨●● 一 ‘”﹂０● ｏ﹁ 一 ●，ｏ﹂くｏ﹂ｏ● も”０〓ロニコ、﹁ヽ ｏく，一 コｏ ■︼ げ″” 一 ∽ 一 Ｆｏ う０●●一 ｏ∽ 一 ︺ＯＦラ一 ｏ● 一 コ一ｏ 一 ヽ﹁ｏ●Ｐぁ ﹁ｏ﹁ 一 Ｌ ﹁ ｏ﹂ ヨ ｑ ε て 一す ｏ く， 一 寿 ０ ●ヨ ｑ ﹂ ●” ‘ ﹁‘´ δ ”●ユ 覇 一 ∽ｏ﹁，くｏ■ 〓 ” ｏ﹁”● 工 ︻ 一ｏ﹁ ｏ ﹁ 一す ０ ぉ ｏげ ｏ﹁” ︵く Ｏヨ 一ｏ二 ，Ｆ ゅΦＯ一﹀ ＞●， けＱ ・３ αヽ ， ﹂ヨ 営 ｏ一 ヽ﹁﹁﹃ｏこ ョ 営 ﹁■ ｏ●ｏ ，αくｏ﹁ ０一一０”ｏ﹂ｏ● つｏ一ゆＯＯＯ ｏ一 ，一 ｏ一＾ ｏ一 一 ，●ｏい，二０●∽一ゴ臼”冒ｏ︻ 一 〓”● ｏＣ﹃ げヽ ”ｏげ一 ︼ ご﹃０ ” パ ヽユ 一 ●ｏ ●Ｏ ＥＢｏ一 場Ｌ一 ０● ︵ 澤と Ｎ８ じ コ ロ，一 ︼ ド 〓０ コｏお 多 Ｒ ｏ●一 ，３“ヨ ■ ざ ●∽ｏ● ・ Ｏ■ ３ ， ま ≡ ＆ 一 暉 ｏＬ讐 ■ 韓 ｏ● 一３ ， コ リ一 ｏＰ ヨ ミ ”３ ■ 一 一 〓９ ｏ●０ ●０■ 一０■ ●¨ｏ︵︺魁一ヽ ヽお ゆＯｏじ ● ０ぐ０︻２ 一一 〇げく 一 一５■６て ，ｏヽ一 一 ０一 ９こド ‘ｏＳ●●９ ８資 ヽ０ ぞ ｏ﹁ 多 ｏ ， 省 ３ ■ 一 ｏ● 多 臓 ∽﹁ Ｓ Ｏ ， ８ ●”ゴ ■ 一■ ９ 一 〓ヽ こし ご← ミ ０ ８ ８ 口３史 ３¨ 、い 暮 ■ ●‘σ一 ヨ”口 ， り ヽこ ご ゛ヽミ 、 Ｏ Ｓ ●゛ど 一６ ●∽ ０﹁ 手 ｏ ，ｏ● く一 ・・∽ 夢 臓 ３ ｏＱ ヽ“， ｏ ヨ と ｏ﹁ ｏ●ヨ ９ ，δ ●” お ＞ くキ お ∝ ８ ８ いｏ﹁る ｏ∽お そ ｑ ｏ こ ｏ●一 を■一 手 “ユ ●一 ｏ﹁ ﹁■ ，ｏ”ｏ● 〓 ，９ 一 ＾ ｏ， ︻， ■ ，“一ご 〓 ゼ ォ げ，８ ヽ ｏう 手 ｏ ｏ０８ ２ ■ ざ ● 一ユくｑ ｏ﹁ ゴｏｏ一 “髯 δ Ｆ Ｆ 一 一 ，一 一ゴ一 一 ＱＯＬｏゴ ０﹁ ∽０く０一，一ｏ﹁●０一 一 ｏ，一すｏ”■” ●，ＯＬく，Ｌｏ● 一 ｏｏ，●ｏ一 ０¨ヽ ，”一 σｏｏ● く，一 ０一Ｏμ﹃２ヨ ０ぃ お０●〓ｏＣ・ ０﹁∽ 丼 一 て ｏ ，”臥 ●髯 こ 一一 ，ｏ ｏ●くε ｏＯｏＯ 二 ︻〓器 一 ８ 降 ｏＯ ︵ げ３ 一 すｏ ∪ ●８ 一 ■∽た ｏ﹁，ｏＯＬ ﹁一 ｏ■ ８ 一 ● ０●■ さＬ ，一一 ●¨ ， ｐ●一Ｆ ∽び ●‘ 一 ミ ヽ， 一いい﹁︶ ﹁‘■ ，９〓¨ 一 ●３ ｏｏ ｏ● ﹃色 ヽお α 一ｏ﹁一オ ●●α 一●∝∽ｏｏこｏ●一 ｏヽ゛０ や Ｓ 一 ｏ﹁， ■ ｏ ォ●０■ ぃ ｏ■ 一一 ド ﹁，ユ す０﹁ 一 す０ 工 ︼く く〓“一ｏｏ ”一 ＾ す モ ０﹃＾ ﹂，９一こ ｏｘ８ う０ 一〓ｏ ヨ ｏら２ 一 〓ｏ一 ｏｏ一●● イ ∽ ，一 ●〓 ｇ ﹂ｏつ ｏ﹁ヨ ２ ｏｏｃｒ ﹃ ”ヨ も一 ●” 一 ｏ Ｏ一 い０，一一 すｏお ■ ，あｏ∽ ，﹃ｏ ，一 うｏＯ ，いｏ﹁ 埓 ２ 一ヽ∽ ¨ すｏ﹁ 一０お コ一 ヽ 一Ｏｏ●ｏ﹁お ｏ﹁●●一 〓０‘ 一，一 一 〇５ 一 ●⊆ ‘α一 ●” ”〓 一 К ヨ ｏα一 ¨デ一 一 ３ ｏ﹁‘ ﹁“一多 贅 ｏ，● い０● ５ ，■ ■ 臓 ざ ， 日す０ ３ お くｏ●８ ０﹁ ， ォ す ２“∽ざ ● オ ８ 営 ３ ｏ，一日●０ 〓 ２ ¨すｏ 一一 ﹁∽ｏヽこ ｏ， ´ 買 菫 郷 一﹃一蜘 請 受 ，． ■ が キ﹃ ． 。詈 ■ ゴ 羮 雛 鴇 ％ い蕗 ぴ 駒 築 難 ¨喘 誨 謁 ■ ↓‘ ｏ Ｏ﹁一 〓 ０●０一，ｏ﹁お０一 ，ｏ ● Ｌ ｏ ，参 ｇヨ ０︵ 一 一 ０コ一 ｏ﹁一 く， 口，一 一 す０ も，一 す０”０● 一 、０︻０ 一 ●０∽∽ ，﹁，一 ∽´ 口，ｏ﹂て，﹂０う ﹁ ｏ﹁ く∽一 一 一 〓 ¨ ■増‘ ヨ 一 参 ご● も， お “″ て ，一 ︻ｏｏよ ｏ， ８ ●添 一 ｏ﹁９δ ●一 ｒｏ繋湯 ●∽ ´ ８ ヨ ，ｏヨｏ粂２ ，う０■， ●２ 計８， ｏ﹁，ｏ一， 譜菱 霙 。 講 誼 呼雌い 舞 請始 鰤審・ ． 婦彙輌 籍勇 訂・ 壼翡¨ 一鍔羮要識 発” 納鷺 髯¨ 軒 鴫︼ 聾 藁鋒 弱 翼 一 ドｒ” ８ ユニ ●”一一 ● ｏ”﹂０●， ■ ，おお一ｏ。ｇ Ｏ●う０●ォ 贅ｏお ００おｏお０一 婚ヽ 藁計韓ミ 疑墨・ 島爆 輝羮報 椰 ヽ ， ， ご Ｏ ＞ 一 静 ｒ ¨ に 一 一 一 ヽ ｏ 言 ８ ｏ ● ｏ ５ ヽ ｏお零 ●ＯИヽ ” ´ 電縄 ゞ奎詳 要涸連記一 講巽・ Ｓ 一 〇 ︵ Ｏ 一 ０ ユ Ｌｏ 一 ︼ Ｌ 〓 一 お 一 一 ● ０ ” ﹃ ｏ ０ ● ， ０ う ｏ Ｏ ｏ ｘ ｏ ︼ ● ∽ ■ い ｏ ヽ〓 〓 忌一〓 き■０こ 霊 ｏ ８ｏ︶ り﹂ こ ６● ｓｉ ｏ ︶ 一 饗覆︷ 率 続難懇鞭鐸覇蹴一 舞 一 ＆ ま ， 〓 ０も”● ３ ８ ョ ●３ ‘ 計 ● ■ ９ ｏご 口 器 お 一 ﹁８ 一 針一 ， ﹂痣 鷺 ‘ ヨ ８ 一 ８ 升 ォ 生 Ｑ ｓ Ｒ “〓 ０一， コ一 メ ３ て一 一 ●■︼くｏ●〓ｏコ・”●０ ，い︼ げｏ●ｏぃ。¨算 ●ｏＯ や ｏ●´ 一すｏ ●ｏｏ Ｏ﹁ す￡ ９ ， 一 ３ ３ Ｓ ｉ 一つ一 ”二 ｏ” ヨ Ｑ ｇ ｏ雰 ｇ げく 多 ｏ ０，一 ョ，いｏ●８ ｏ﹁，● ｇＲ３一Ｏｔ，おＬ ヽ０くｑ附 ︻ ｏ，８ざう ０︻”●ヽ Ｆｏ■一 ヽ ︻ ｏ一 ｏ，Ｌ〓０●●曇﹄”お０すｏＮＰ ︻ ， ｐ〓︶ ﹁一 ‘δ ， ０一ｏ 一ゴ，一 ０●一 ＯＯ∽， ０いげ ０﹂ くｏ●０´∽ ，５，一 ︼９ ∽ ・ ０ げ０げ●ｏ ョ■００〇一Ｌｏ●一””ｏ●一∽０●︼ ，” ＯＯ“一 ０〇 一０●一 ０，く¨ 一 く。一 ωｏＳ ｏ﹁ｔ ，おお〓ＩＰ ，一 Ｐ∽ ざ●∽‘ちＯｏく０３。゛てｏ一﹃ヨ つＯｏ〓 ↓ げｏ一ｏ 一一●，ａｒ ａ ｏ●け ■ ５ ヽ 一 一 〓 くｏ 日 二 一 い ■ ●〓 ヨ ， ‘ 一 一 ●くｏ一 ¨ ｒＯ■ 一 一 一ｏ Ｏ一﹂ｏ ● ｏ”●０〇 ｏ コ３・●一 ●一 ”﹃ ０●０∽ 一 ¨ ﹁ｏＯ﹃ ∽ ０● 〓 ，ｏ ，ｏＯｓ ヨ，︶ ■９８● ｏ モデ９ｏ ヨ２，一 ９， ０毬ｏ ８ 〓 ０●ｏ協 一 〇０∽一 ご ｏや９ ０ ｏ﹁ 〓Ｏにｏ， 一 ざ ， ｏ﹁ ０，一 お 鶴８ 一 口，８ ■ ，一 ■ ３ ● ‘ｏ傷 ■３ ８ Ｌヨ 髯 ｏ０ ２ ６歓 ヽ ｏｏｏ もｑ ■ ，お一 ｏ一 一 ｒくの 一 ”﹃ お●一¨﹃０●一´ ● ● ■０﹄ ，”ｏ ﹁０﹁一 Ｏｏ﹁”一 ¨〓お０ ″くｏ﹁ ，８ ｏ●■ ョ ” ∂ ” 一ｏＳ ０一 て９ ｏ﹁ ∪ ●８ す ｏご 一■ ■ ¨３ ・∽Ｐ ∽ざ ， 一 一 ６ ぞ 〓 ¨ゲ 鷲 一 ８ 一雰 ， ュ ●お ヨ ¨ ８一 ｏ一 ｏ３ ，一 〇７ 把西 邦ゴ絆筆艶嗜鋒鶴学一 ¨ 一 や 雲¨ 斃発¨ 準醜醍 ・ ∂ ︻もヽプ０”ｏ，Ｉ●■〓ｔざ一■ ，К８っｏ， ヽ８ ｏも， ⊆ｏｏｏは ， ⊆尋 ３ ６ 澪 ‘ 〓 ，ォ ‘ ｏＬ﹁ｏ営 Ｓ 一 〇 ８８ 壺ヽ ， ■ ヽ３，，一 電 ｏ Ｒ ｒ， ヽヽ さミ ミ ヽ ミヽヤヽ ・昴 場Υ一 ＞ ０＾Ｚ Ｏ選、 ｒ“∪ ０ 〓一 いＺ ↓∽ ↓〓け ヽ¨ す てヽ ﹂げ 一 ｏ ０ ● ｃもヽｏ■一 ｏ ヽ﹃ ヽ コ， ｏ﹁”Ｂ二０ ﹁ ︶¨﹁ キ一 一 ︵ ， ∽ ・〓●８﹃ ‘， じ ，コ０ 一 Ｉ ∪〓３ ″一 ﹁， ﹁０■●﹂ヽ﹂ｏｏ﹁ ＯｏＱ 弓ヽ ﹁ ァ︵ ”一 一 ０● ”ｏ ヨｏ ０ ０ ヽ ヽ Ｅ ∽ ∽ ０ ０ ● ヨ一 ﹁ ”﹃ ８喝︶ くｏ３なうｏ三ａ零 多Ｆ ａく一 ８ ０﹁ｒ ０〇一 〓 ， Ｏｑ● ＞︶ヽ ︵ ， ０＞ヽＣ∽ 一ＯｏもｏＳ一ｏ ｏ ﹁ ヨ●０響 Ｐ ｏｏコｏ ュ０“ま ］びｏＯ ∽‘一●ぞ ﹁●●●Ｏｏ ∽ ∽ド 一 ヨ〓 ′げＥヽ ︵ ０， 一 一 ＞ヨ∽ ﹀＞ も営一ｏ﹁手お い ｑや員ｒ手ｏＺＲすｑご●０﹂ ●ｅ 口０ゆ ｏ 一ゆ︼ ∽”↓Ｏｏ，お■ て， ぞ０︻ ｏ ∽ ｏ ● ｏ０８二０●∽ ｏ ●ｏ ●ぉ０●一一 一 ０ ﹁〓 一 ● くヽ ● ８●６一Ｔ， ● 〓‘一 β 〓Ｃ ＣＯ ダ、 ５ ﹂ ∽Ｆ” 菫●‘´ Ｃ ， ”０■３Ｐ ︼ 二■ ︵ ｏ ｏ ゃ じ ヽο ︼いミに・¨い ＆零 手ｏ ヨもＬ ｏ﹁ 旨０﹁〓 ジ ‘゛ くｏ 計す ｏモ︼ ︵ ，げｏ こ ︵ ”﹃ オヨ， ， ０， く 〓ｏｏ” 工ｏ 一 一 ８ 一６ｏ くｏ コ一 ， ８・ ． ． ． 語 地 肝 聾 霙 鐸 翌 鶴 鶴 一〓 ■ ■ 。 ”け﹁国”●Ｚ のい∽ Ｋ ・ メ§ 〓⋮ Ｊ ・ ζ ＞Ｌ ”● ¨薫 ︰ 毛 Ｆ 露 ´ ョ ｉ ｔ ｉ ｌ デ く Ｌ Ｌ Ｆ モ ︺凛 っ０３ ０ｏ一 ぞｏ●甥一ｏ〓‘ョ”●”ョイ ＨＯ●くｑ”禽´¨レト ︵︻ 一 ６﹁８＾ ≧Ｂ す ＾ 訂 Ｚｏ一 ，■ ８ ０ ｏヽミ Ｌ ´ 一 ︼ ︼ｔ 一い０ ，”，一 ＞‘”●０ す０， 一” ， ”〓パヨ０マｑ一■Ｕ 含っっじ ∽，おこ ，コＯｏ ， ｏｏ 年 にｏコ´ ∝ ，，■ ， Ｆ ■■ ， 征 Ｏｏ う０∽ ∽ 亀 ６︼ く０ ●一 ‘ 富 ”一 ｔ ｏ ３ ｏ﹁ ， ぶ８ ま 弁 σ一 ８ ０ そ一一ｆ む ミミ 、 ミ Ｓヽ ８，﹃ ヽミミヽ ゛゛ い送Ｆ馬 ８上 営 ● Ｒヽミ♂ヽ８ヽヽヒｓヽきヽ ＞‘”‘ｏすｏＰ ヽ”・”一 丼 ヨｏ もっじ てｑ・■υ 針 ”易 〓 ζ お ︵ ０９一 ，お●９∽ｏ﹁ｏｘ一ｏコαｏ α〓Ｃヨヽ一一 一 お露︶ ｏ ８ ｏヽ ■■●，ｏ一ｏ﹁０ ‘ａ■ ｏ〓 品 ０８ ８８ ´ ∂︻００●■８ σ一 ヽ ●●０ ギ ミ 崚ゞい ８・ ０１ 一一 いヽ・本 ”ｏ 実 ９´ ”＞ ︵ ８ ｏＯ ”〓 一 一 ２ ｏｏヨヽヨ〓〓一 一 ３ ｏ﹃ ●● ｏ﹁，２〇 ざ●¨ユ一 マ一ヽいｏ 一ｏ● ｏ﹁∝いｏ‘ コ●ｏＯ●ｏ ｏＯョヽ●コ０ ●●¨”●３●ｏ ﹁一 ■ ，一〓︻ 一 ８コ一 “ くｏメＦ ヨ“■●′ “， 〓 摯 いｏ︼ 一 Ｆ Ｏ 口・く ｏ ，おこ・﹄ｒ ・”，おヨ，ユ て ﹁ヽＯｏ品ｏＣ・０・ すｏ´・ ∽Ｓ”〓●●´こ ， ”，∽ Ｏ ｒ共やＯｏじ のｏ３●黎ｏ ，７一●３∽ｏ” す０”ｏ● ヨ，９７，一 ざ， 一 Ｐ∽ δ３・ ３ 一 ヨ σざ００ ●ごお一 Ｓ３一 ヽ”´ や 、 Ｓ ヽヽ ミヽ ミ しＬК ■ 一 ＞‘汗Ｆ一ｒ や ﹁，´ ”●´ ︸〓じ く ８０ こ ， ヨＰ ｇ■ ︵ ”二∽ ｏＯ‘ヨニユ” すｏ，〓ゴ σｏ，０●一 ， ， うｏく０一，一ｏヽ Ｏ●０プ ´ ｏ Ｏコ一‘﹃ ０ ■ ０一ｏ﹁Ｓ 三 編 Ｒ Ｓ Ｓ ●〓 ３ 一霊 ＾ ８， さ 言 、 ■ ミ ， ０・、いい 116 ０一一らヽ，∽・ ０一 ”﹃０‘０一・，００●“●■●” ﹁ｏ﹃ ＯＯ゛ぃ ０﹁ ∪ Ｃ８ す ｏ一 ｏ一 Ｐ り一 ＞ ６ ﹃お Ｏ Ｓ 一３ ｏ﹁ りｏフ オ モ ｏ■ ａ Ｓ 一 一 いｏｏ ３ ｏヨ 386 M, J. Postma et al. Cost-effectivenessof pathogen inactiyation fu platelets @2005BlackwellPublishing Ltd, frawrrton Medi.ine,t5, 179-387 Achieved,lryfel Is to Be Expected?(eds Smit Sibinga, C.Th. & Cash, J.D); pp. 45-51. Kluwer, London usBN 1402000?901. Postma,M.J., Staginnus,U. & RuitenbergE.J. (2001) Pharma@-ecotromi$of-blood transfusionsafety measures:'a review.of tbe litentLurc.Valuein Heahh,6, 476, Postma, M.J., Wiessjng, L.G. & Jager, J.C, (2001) Pbamaco-economicsof drug addiction; estimatitrgthe costsof hepatitigC virus, hepatitis B virus and human immunodeficiencyvirus iilfection among injecting drug users in mcmber States of the European Union. Uly' Journalof on Narcolics,53, 79-89. Postma,M.J., Wissing, L.G. & Jagcr,J.C. (2005)Updaled healthcare costestiihblcsfor drug-relatedhepatitisC infrctions iD the EuropeanUnion. ln: HepatitisC andInjecting Drug UEe:Iilpact, CostsMd Policy Aptioro (edsJager,J,C., Limburg, L.C.M., Postrna,M.J., Kretzschmar,M.A.E. & Wising, L.G. EMCDDA, Lisbon, 203-216. PrimantHeilth Care, Utrecht, data extracted.fromfile for ICD.code999.8for 1998-2002. Riteco,J.A,, de Heij, LJ.M., van Luijn, J.C.F.& Wolff, I. (1999) Guidelinesfor Pharmaco-EconomicResearch (Richtlijnen voor .Fsrmaco-economisch Ondetzoek (ln Dutch)). Health Care Insurane Board, Amstelveen (Netherlands). Robillard, P. & Karl Itaj, N. (2002)Incidenceof adverse transfusionreactions(ATRs) in the Quebechemovigilane system.- ye! 2000. Vox Scngutnis,83 (Suppl. ?), I 20. SanquinBfood Supply Foundation (2001)Annual Report 2000.Sanquin,Amsterdam. Saama,K. (1994)BacteriaiD blood for transfusion;a review. Archives of Parhology & LabordtoryMedki.re.| 18,150-365. Schmid, A., Burchardi, H., Cloirth, J. & Schneider,H. (2001) Burden 9f illness impowd by severespsis in Germany.Valuein Health,6, 443. SeriousHazards of . Transfusion (SHOT):' Annual Repon I 999-2000.SHCjT,Manchester. Struijs,J.N., de Wit, G.A., Kretzshmar,. M.E.E., Smits, L.J.M., PgstmaiM:J., van de Laar, M.J.W. & Iager,I.C. (2000)Costsand eff*ts of univerealyadcinationagainst @ 2005 Blackwcll Pubfi shing, Ltd, Tra6lwion Mediciile, 15, 379-387 hepatitisB Kosteo cn effectenvan universelevawinatie tegenhepatitis B) (in Du!ch). Inlectieziektetr Buuetin,ll, t09-l 14. The BypassAngioplastyRevasculariationInvestigation (BARI) Investigators.(1996) Comparison of cbronary bypasssurg€ry with angioplastyin paticnts with multi. vesseldisease,New EnglandJownal o/ Medicine,335, 2t'7-225. Van Gestel,A., Bakker,J.,Veraart,C.P.W.M.& Hout, B.A. (2002)The costs of severesepsis;the Netherlands2000. Valuein Health.5.56l. Van Hulst,M., de Wolf, J.T,M.,Staginnus, U., Ruitenberg, E.J. & Postma, M.J. (2002)Pharmaco-eoonomics of blood transfusionsafetyj.reviewof the availableevi' denq, Vox Saagvu6,83,146-155. Van. Rhenen, D., Gulliksson, H., Caanave, J.P., Pamphilon,D., Ljungman,P. & Klueter, H. (2003) Transfusion of pooled buffy coat platelets prepaied with photochemial pathogeninactivationtrearment: the eUToSPRITEtnal. Bloo4 l0t, 2426-2433. Welte,R. & L€idl, R. (1999)Transferof relultsfrom foreigneconomic+valuation studiesto Cermanyrproblems and solutions (Ubertragung der Ergebnisse dkono. mischer Evaluationsstudien aus dem Auland auf Deutschland: Probleme und . Lisungsansetzel in German). In: Ansdtzeund Methodender dkonomischen Evaluation- eihe intetMrionale Pe$pekrive(eds Lcidl, R,, Graf Vm der Schulenburg,J.-M. & Wasem, J.). NomosVerlagsgesellschaft, Baden-Baden. Yeh, J.M., Bottman, M., Pashos,C,L., Posima,M.J, & Staginnus, U. (2002) Economics of transfusion. Trwlwlon Medicire, 29, 218-225, Yostovian, R. (2002) Novel methods for deteotion o[ platelet bacterial @ntamination. Vox Sangulais, 83 ( S u p p l .) . 1 2 9 - 1 3 1 . Yomtovian, R., Lazarus, H.M., Goodnough, L.T., Hirschler, N.V., Monissey, A.M. & Jacobs, M.R. ' (1993)A plospetivc microbiologicsurveillancrprogmm to det4t and..preventthe transfusionof bacterially@ntaminaled platelels. Trqrcfutior, 33, 902-909. 卜［Ｈ Breher, M.E., Aubuchan,J., Yomtovian,R., Ness,P.M. Michel, B.C., van Hout, B.A. & Bonsel,G.J. (1994) & Blajchman, M.A. (2002) Open letter to the blood Asssssingthe benefitsof transplant sewies, Bailliire's collection community. The University of North Clinical Gds*oentetology,8, 411423. Carolinaat ChapelHill. Morrow, J.F., Braine,H.G., Kickler, T.S., Ness,P.M., (2001) Ciaravino, V. Preclinicalsafety of a nucleic acid' Dick, J.D. & Fuller, A.K. (1991)Septicreactionsto platelet transfirsions;a persisteDtproblffi, Journat of targeted Helinx compound; a clinical perspective. Seuinars ln Hematology,38(Suppl. I l), l2-!9. the Amqicil Medicql Associatioa,266, 555-558, Coebergh, J.W., Capoeccia,R.. Gatta,G., Magnani,C. & Miiller-Breitkrcutz, K. for the EPFA Working Group on Stiller,C.A. (2001)Childbood mncer survival in Europe, Quality Assurane. (2000)Resultsofviral marker scren1978-1992ithc EUROCARE study. EuropeanJournalof ing of unpid blood donationsand probabilityof winCancer,!7, 681-694. dow period donations in 1991. Vox Senguinis,78, Corash, L. (2000) lnactivation of viruses,bacteria,proto149-15't. zoa and leukocytes in platelet concentrates.I/ox Ness,P.. Braine,H., King, K., Barrasso,C., Rickler,T., Soaguinis,78 (Suppl. 2), 205-210. Fuller, A. & Blades,N. (2001)Single.donor platelets Gold, M.R., Siegel,J.E., Russell,L.B. & Weinstein,M.C. reduce the risk of septic platelet transfusjonrsctions. (1996)Cost-effectiveness in Heahh and Medicine.Oxford TrusJwion, 4I, 857-861. Unjversity Press,New York. Oostenbrink,,J.B., Koopmanschap, M.A. & Rutten,F,F.H. Health Council (GezondheidsRaad),(2003) Pathogen (2000) Guidelines for Cotting: Method.s and Stsndard reduction in blood products. Heatth Council, The Pdces for Economic Evaluations in Health Care ( Richrlijnen Hague. voor Kostenschattingen it de (2001) Hjelmgren,J., Berggren,F. & Andersson,F. (in Dutch). Health Care Insurance Health Gezondheidszorg e@nomic guidelines- similarities,differencesand some (N€therlands). Board, Amstelyeen impficalions. Vqlue in Health, 4, 225-250. Op de Coul, E, (2001) AIDS in Nederland2000 (AIDS jn the Netherlands; Kuehnert,M.J., Roth, V.R;, Halsy,N.R., Gregory,K.R., . in Dutch). RI\M, Bilthoven (Netherlands). Scheiber, G.B., Arduino, M.J., Holt, S.C.,Carson,L.A., Elder, K.V. & Jawis, W.R. (2001)Transfusion-trans- Owens, D.K. (1998) Interpretation of cost-effrctiveness mitt;d bacterial infection in the United States,I998 analyses. Jounal of General Intemal Medicine, 13; 'il6-'il7. rhrough 2000. Trunsfwion, 41, 1493-1499. Lin, L,, Cook, D.N., Wiesehahn,G.P., Alfonso, R., Percira,A. & Sanz,C. (2000)A model of the h€lth and Behman, B., Cimino,G.D., Corten,L., Damonte,P.8., eonomic impait ofposttransfusionhcpatitisC: appticaDikemn, R., Dupuis, K., Fang, Y.M., Hanson, C.V., tion to cost-effwtiveness analysisof fudher expansionof Hearst, J,E., Ljn, C.Y., Londe, H.F., Mdtchette, K., HCV sreening protorcls. Translusi on, 40, I I 82-l I 9 l. Ncrio,A.T., Pu, J.T., Rames, A.A., Rheinschmidt, Perez, P., Salni, L.R., Follea, G., Schmit. J.L.. de M., Tessman,J., Isas, S.T., Wollowilz, S. & Corash,L. Barbeyrac,8., Sudre, P. & Salamon, R. for rhe (1997)Photochcmicalinactivationof virusesand bacteria BACTHEM Group and the French Haemovigilance platelet in mn€ntrates by ure of a novel psoralen and Network. (2001)Determindntsof transfusion.associated long-wavefength ultraviolet light. Trawfusion, 37, bacterial contamination; results of the French 42J435. BACTHEM case@ntrol st\dy. Ttwfusion, 41, (1992) photoL.; Lin, Londe,H. & Hanson,C.V: Psoralen 862-8'/2. ichemical inactivation of freo-ell HtV-l in platetet conPostma, M.J. (1998)Asessrcnt of the EconomicImpact of *ntrates is arrelated with rhe inhibition of reverse Aids at Natiffial and Multi-national Lael; Dgvelopment tanscription using an RT/PCR assay.Blood,(Suppl. l), of a Scenerio-analytic Approach to Support Health-care 223. Pollcy. Koninklijke Wtihrmann bv, Zutphen. (Academic Lopez-Plaza,1., Wcissfcld, J. & Triulzi, D.J. (1999) The Thesis) aost-effectjveness of reduciig donor exposureswith sinPostma, M.J., Bos, J.M., v?n Hutst, M., Smit Sibinga, gle-donor versus pooled random-donor platelets. C.Th. & Rujretrberg,E.J. (2002) Phamao{cdnomics Trmsfusion, 39, 925-932. of nubleioacidamplificationtesting(NAT) of Dutch Loubiire, S.,Rotily, M., Durand-Zaleski,l. & Costagliola,D. blood donors for HIV. XIVth InternationalAIDS (2001)Including polymeras chain reaction in screening .. ponfercnce,Barelona, abstractTuPeC486l. for hepatitisC virus RNA in blood donationsis not cost. Postma, M.J., Heijnen, M.-L.A. & Jager,J.C. (2001) et!*tive. l/ox Sugu,hr's,80, 199-204. Cost-effectiveness analysisof pneumococcalvarcination Mccullough,J., Vesole,D., Benjamin,R.J., Slichter,S., for elderly individuals in the N€therlands. jnactivated Pineda,A. & Snyder, E.L. (2001) Pathogeir P harmacoeconomics, 19, 215-222. (INTERCEPT platelets(plt) using HelinxrM tcchnoiogy Posrma, M.J., Smit Sibinga,C.Th. & Ruitenberg,E.J. plt) are hemostatically effective in thrombocytopenic (2001) Phamaco-economicsof transfusion safety. In: patients(tcp pts): the SPRINT Trial. 8/ood,98,450a. Trcnsfusior Medicine: Quo Vadis? What Au Ben 387 :。 rr■り し∫ "Meaic姥,20116,'6,17-30 do1 10 11111 136S.3148200600644x 0RIGINAL ARTICLE に T'1'耳 ハ P':￨° 'i:1111:1llili'':l。 Iザ li91allillll:・ ,1 nlcⅢ*￨￨″ 酬 a‐ PITギ Ⅲlθ r"'ヤ γ 111′ ″ ∬11'I'1壼 γ :オ lド ￨IZ「 稔 ボ 11今 TL7: i・ lf""° ゃル,ぉ赫“レ却4 eFCq″ ″ル2HbⅢ bα ル,2oo, Ⅲ 2′ SafC,y ahd cOsts wc"obtained from Ottcial sources HepaJls C vlrusJike emer」 ng pathogtt waS,Inulated 7ed,highly Key words: emerging,. INTERCEPT, ^WidC ralge Of ICERs■ as obser■ Scnsitivc to the riSkerging of o口 pat10gcn trans‐ vation, platelets, safery, fiansfusion The risk of transfusion.associated viral infectionshas been significantly. reduced.by the introduction'.of donor-screening and blood-screening tsts in routine practice.However,someresidualrisk of transfusion; relatedinfectionsrc,mains. This is because of the wirrdow penodbetweeninfectionand positivetestiEsults the on onehandand to somepathogenswhichcould potentially be .transmittedvia transfusion,but for whichscreening tests.a.re not pgrformedtoday on the other hand (e.g. Cytomegalovirus[CMY], Human T-lymphotropicvirus [FITLVJ...). In addition,viral sareeningtests mai produce false-negative resultS (Lapercheet a1.,2003;Busch,2003).Recently,safery measures havebeenincreasedby includingNAT tests for hepatitisC virus (HCV) and HIV detectionin routinescreening programs.However,currentsafety Correspondenci:Dr KaE[ Mocrcmans, HEDM, Craygntraat 5.' 1000 Brusscl, Belgium. Trl.: +12 3 E996l 19; far.+!2 3 899 61 09; e-mail:[email protected] O 2006 Blackwell Publi6hing Lrd palhegsn in3gti- initiativssconsistingof serologicalor viral antigen testsaddress<inlyone or few selected pathog€nsat a time.Any newpathogenrequiresnewsafetymcasures in additionto the alreadyestablished syst-em. Historical as well as contemporary.dataconfirm that the risk ofnewly.emerginginfections is nothypo- , thedcal(WHO, I998 (w.who.int); Leiby,European ?arliamenthearin! June,2003;Biggerstaff& Petersen, 2003).Dependingon their'clinicalcharacteristics and modesof transmission, theseemerginginfectionsmay presentan enormous threat td iransfision safety: Scientific. informationis often limited at the time of emergence, and the development ofdiagnosticscreening teststakestime, Therefore,theseemerg:ing ageits requirenovel approachesto irevent transmision (Leiby,.European ParliamenthearingJune,2003). As they are stored at roorn kmperature!platelets are particularlyvulnerablefor bacterialcontamination. Therefore,bacterialscreeningis routinely per, formed on platelet samplesin Belgium;however,a potentialrisk of false-negative resultsremains. t7 ∞Ｈ日 mission, underlying disease and age. In the most conservative approach, ICER ranged from 辮 :良送需 践::『鵠 sttdぽ 観 t認 li鶏 3,459,201€/QALY in absence of emerging paLhogen iⅢCIVatcs pathogcn、 alming at clminaung thc‖ sk ro 195,364€lQALY. The mean threshold of emerging 。「lransmiting cllrrent inl emCttging pathogcis Thc infection risk for trBSPdominance (saving money and obJcctivc was t0 0,aluatc thc incrcmcntal cOst‐ producing health gains) ranged from l/1,079 to efFe← tivencss ralo(ICER)fOr IBSP in,dgium l/2,858 ttansfusions. A decidOn modci compa■ ng a`WOrid with IBSP'to Considenng the high value auchoriries appear to a`"o■dw“hout BSP'calclllatcs ltlme and cOsぉ place on preventing accidental injury, and ICER of `quali"adJuSted liFc,carS'(QALYs)fOlloWing platelet rec€nt implementations in transfusion m€dioine transfusion in difrcrent indicatiOns biscase‐ specinc lire (NAT: up to €2.3 million per lifeyear), IBSp can be c21pcctancy and∞ nscquences oftransfuslonitransmlted considered cost-effective, taking into account the infeCIons were Ob“ ned iom l"raturet TFanSrusi。 . potential risk of emerging pathogens, 18 K. Moeremm The INTERCEPT Blood System for platelets (IBSP) is a new technology which inactivates different types ofpathogens through irreversible binding to RNA/DNA in the blood (BioDrugs,2003). When new safety measures are introduced, there is clearly a need to accurately de{ine lhe value of these new initiatives, and decisionsregarding bloodscreening policies murt be based oD accurate estimates of the increm€ntal saf€ty balanced against cost and taking into account the potential loss of donors {Busch et s|.,2003\. The objectivo of our study was to analyse the health and economic consequenc€sofpathogen inactivation using the IBSP in Belgium, taking a perspective directed to the future, including the risk of emergence of a new transfusibn transmittable virus. SUBJECTS STUDIED METHODS We performed la cost-effectiveness analysis in Belgium from a societal perspective, including both direct medical costs and productivity related costs (expressed in euro), as well as legal and.liability costs. A decision analytical model was developed simulating the clinical outcomes of patients requiring platelet transfusion, in a world with and in a world wirhout,the INTERCEP-T blood sysrem. Model The model was developed using T*reAce orrnru software. The model starts at thd time of platelet transfusion and simu'lates the evolution of a cohort of patients receiving transfusions of platelets inactivated with the INTERCEPT blood system compared with the same cohort receiving untreated platelets, taking into account the risk of bacterial infection, HCV, hepatitis B virus (HBV) and HIV infection. These infections are cunently tesled for in Belgium blood syttem 19 and their residual transfusion-related infection risk has been assessed. In addition, the risk of a possible newly emerging viral infection is included in the framework. The overall risk of infection per patient is calculated in the rnodel as the risjdual risk per transfusion multiplied with the average number of transfusions per patient. If no transfusion-related infection occurs, the average life expectancy is the one of the underlying diseases. If transfusion-relaBd infection occurs, the life expectancy is reduced because of the mortality associated with the infection. The main decision analytical model structure js outlined in Fig. L LiIe expectancy in the absence of nansfusion-retat:ed infection The average life expectancy associated with the considered underlying diseasEswas calculated based on published mortality rates. By applying yearly mortality rates, average life expectancy can be calculated as the surface below the survival curoe. For both ALL and AML, I year mortality was 44% (Dini et al,, 2001). During subsequent years, the relative mortality rates as reported by Soci€ et al. (19991 were applied.to age-matched general moitality rates in Belgium (1997). In patients with NHL undergoing early stem cell iransplantation, a 5-year overall survival rate of approximately 657o is reported (Dresse et al.,1999t Martelli el a/,, 2003)..Patients surviving more than.5 years were assumed to have normal life expectancy. In CML patiena, based on review of rec.entliterature (Carreras et al,, 2000;.Davies el al., 2001; Elmaagacli et a1.,2002; Gaziev et a1,,2002; Pigneux et a1.,2002:,Radich et a/.,2003), an averagecurnulative mortality l'ate of 50yo by year five was estimated. For the remainder 50olo,long-term relaiive mortality rates were applied to the age-matched general population (Soci6 et al., 1999).. For CABG patients, a weighed averagelife expectancy was calculated from data published by Weintraub et af , (2N3), including mortality rates up to 20 years post-intervention. Although these patients were operated many year's ago, th€ short-term mortality was not highgr than reported in more rebent studies (Calafrore et al,,20M', Taggart et al., 2001). For breasJ cancer patients undergoing Peripheral Stem Cell Transtllantation (PSCT), life expectancy was estimated equal to the weighed (for study size) average median suwival reported in PSCT patients (Farquhar et al., 2003). PublshingLtd, Trmq[usiot Mediciae, 16, 11-30 @ 2006Blackw€ll ＯＨＨ The target population included patients with haematological malignancies undergoing bone marrow or peripheral slem cell transplantation [acute lymphoid leukaemia (ALL), acute myeloid leukaemia (AML), and nonchronic myeloid leukaemia (CML) Hodgkin's lynphoma (NHL)], breast cancer patients undergoing stem cell transplantation and patibnts undergoing dardiac surgery, whereby coronary artery bypass graft (CABG) was selected as case. These populations are considered to receive most commonly platel€t transfusions (Bell .et al., 2003\, MATERIALSAND Costeffectiveness of INTERCEPT et al, Fig. l, Basicstructw of drcision tree.QALY, quality adjustedlife years Table I sunlmarizes the obtained average life expectancyper underlying disease. Risk o! known infections with untrcated platelet comPonenE Table 2 provides an overview of viral safety ti?stsperformed on blood components in Belgium today, the fiequmcy of positive tests and th€ respectiveresidual risks ofviral transmission per transfusion (Beigian Red Cross2003,se Acknowledgements).As they are stored a! room tenperatule, platelets are particularly wlnerable.for bacrcrial conlamination. Therefore, in Beigrum, a sample o[ the platelet component is monitored for O 2006Blackwell PubliBbineLtd.Tr^slginn Ueditae, t6, It-10 bact€rial contamination throughou! storage timq using the 'BactAlert system', Becauseof the absenceof mandatory reporting of any transfusion-relat€d ev€nts, there is limited information on the actual risk oftransfusiolrassociaed bacterial infecuons in Beleium. For the cunent analysis,Red Cross and clinical Jxpert estimates were collected. The most gonservativeestimate,reporled by the Red Cross, was a rate of transfusion-associated bacterial infections of one in 5000 transfusions. Rbk of emerging pathogem To assessthe potential health emnomic consequenc€s of the INTERCEPT blood System, the risk of future 20 K. Moeremansst al. Cost-effectiveness oJ INTERCEPT bloodsystem 7l Tablel. Averagelife expectanoy in the absence of trans' fusionrclatedinfectior Average life T,pe expectancy (years) AML aduts AML chi:dhood ALL adults ALL childhOOd ´ NHL adults NHL childhOod CML CABG Breast canccr 17 319 3■ 1 5 6・ 59 26・ 3 96 161 27 ALL, ailte lymphoidlcukacmia; AML, acutemycloidleuksemia; CABG, coronaryartery bypas$g.aftr CML, chronicmyeloid leukaemia; NHL, non-Hodgkin's lymphoma Effcacy and safety of IBSq The following path6gens are inactivated by the system (approved indications); HIV l, HM, HBV, HCV, CMv, MCMV and aerobic bacteria. The following inactivation claims have been recently approved by the Irish Medicines board: HTLV I, HTLV II, Trepbnema pallidu,m (Syphtlis), proiozoa (Trypanosoma cruzi, Chagas disease,Plesmodim falciparum, malaria) and anaerobic bacteria, Other inactivation studies on dltemative pathogens are ongoing (Leishmaniasis, Babesiosis,Qandida atbicans, Boruelia bugdor/eri, West Nile virus, Paruovirus Bl9 - last update July 2004). The results of an extensive series of lz yitro and !n vivo studies have not demonstrated any toxicologi€lly relevant effects on platelet concentrates prepared by the INTERCEPT Blood System (Ciaravino et. al., 2001). In the model, thg inactivation system is progrdmed to eliminat€ the risk of the considerdd known transfusion transmittable infections as well as to eliminate transmission of the simulated emerging virus. Two main assurnptions under'lying thd model were that Tsble 2, Viral safety.measures and residualdsk of platel€ttranslusions(Belgium) Screeiringtest HBV HCV HIV : HbsAg Anti‐ HCV NAT Ahti,HIVl and 2 NAT HIVl Donations (Wallonia, 2002, seeAcknow)edgements) Donations (Flanders,2000, seeAcknowledgements) Tested+ True + Testcd+ 54/100,000 93ノ 100,000 l η1 0 0 , 0 0 0 17/100,000 1 2 1 / 1 0 0 , 0 0 01 り1 0 0 , 0 0 0 119/100,000 6/100,000 111/100,000 0/100,000 103/100,000 True + 03ハ00,000 Rcsidtal risk拿 1く/ 2 0 0 , 0 0 0 く 1/200,000 1/703,571 く 1プ ト3 mio く1/4 6 mio HBV, hepatitis B virus; HCv, hepatitis C virus SouG: B€lgian Rcd Cross. 'Risk of fa;smisior\p€r'transfusioh'. @ 2006 Blackwcll Publishing Ltd, Tt@rhsion Medicine,16, l'l-30 Fig, 2. Structureof sublre related to tmnsfusion-transmittcd inf@tion with hepatitisB or C. Under each bmnch,th€ probabilityoftransition from the left to the right healthstateare shown.The probabiljtjs undertbeleft hand sjde branchs represnt possiblepathwaysat model start;at the lime ofinfection. At this time, patientsein eitherhaveonly acuteinfectionwithout be@minga carrier QoVo)or Vcome @ftier (80Y.j. Subsequ€ntly, eniers may develop chronicomplietions, posibly evolving over chronichepatjtisto cirrhosis,liver failure or carcinoma.Thc probabilities shownundertheright handsidebranches representthe likelihoodof possibletmnsitionsfrom one stateto another.The probabilitleswae obtainedfrom pub. Iishedliterature(Parcim,2000;Sevinir, 2003;Girdon, 1998;Hu, 1999;Tong, 1995). Onlytheprobabilityofdeveloping chronichcpatitisis diffqeot for HCV vereusHBV:0.212 (Sevinir,2003; Psreim,2000)and 0.224(Sevinir,2003; Gordon, 1998)resprctively.Other dis. ese progrcssiol rat6 wer! programed equallyfor HCV and HBV. HCCA, ' Asympbrutic ceier Chronic hapatitis Cirhosis Chronichepatitis Cirh6is Liver fsilur. HCCA HCCA Dcath Livertsihre HCCA Derlh hepatoetlularercinoma. pathogen inaqtivation is 100% effective and is not associatedwith major or costly adverseevents. Additional benefits of the IBSP The INTERCEPT blood system is anticipated .to have an additjonal number of future benefits, supported by a recent. international forum of experts (Engelfriet et al., 2003). First, it is estimated that, in the future, some of the currently applied screening tests, leading to platelet waste, may be eliminated. These may include BactAlert testing, NAT testing (given the high burden and low yield) and Alkaline Phosphatasis(ALT) testing. It must be noted that, at present, the elimination of NAT testing is only possible.for siirgle donor platelets, becausefor ra4dom donor platelets, the tests are needed to ensure safety of the obtained red cells and plasma. However, pathogen inactivation for red cells may become available in the future. Neverthelbss, given the uDcertainty of its timing, in .a secondary analysis (not in the basecase), we considersd this potential benefit only for Single Donor Platelets @2006Blackwcll PublishingLtd, TtNf6ion Me&cinq16,11-30 (SDP)platelets.Secondly,studieshavedemonstraled that the INTERCEPT blood systemis at least as effectiveas f-irradiation for the inactivationof Tcells(Lin et al,, 1997;Grassel a/., 1998).Hence,the secondpotentialbenefitmay be to rhakef.irradiation, which is performed on the majority of platelet componentsin Belgium loday, obsoleto.. The third benbfit consistsof a reduition of platelet wasle. Today,in Belgium,of the 41808 platelertransfusion bagsdorlatedannually,approximately8% 4rewasted o[ storagetime overdueand 1.9% because because of contaminationor positiveviral screeningtests(Red CrossBelgium).In the past,the plateletstoragelime initiallysetat 7 dayswasreducedto 5 daysmainlyfor increasingrisk i:f bacterialcontamination.With the INTERCEPT blood system,the previouslyapplied Iimit of 7 dayscould.poientially be re-introduced. In addition to the above-mentioned current potential b€nefits,pathogeninactivationqay avoida proportion of supplementarytests in the future for potential emergi4gpathogens,which will not be requiredfor SDP,Conservatively, the latter benehtis not consideredin theeconomic evaluarion, 〇銀 Ｈ known or unknown emerginginfectionsweretaken into account,Becausethe characteristics of a new emergingvirus are unknown,it wasdecidedto simulate an economic,inorbidity and moltality impact Qomparabl€with HCV, The simulationof infection risk lor this new emergingvirus can be basedon the historiel eriolution of HCV virus transmission through transfusion, although it could be argued that, comparedwith the .1990s,a new virus today would be identihed sooner after its emergence becauseof scientificprogress,and hence,that transmission rates will probably not reach the level obsgrvedfor HCV at the time. But, on the oth€r hand, a lot dependson th€ diseasecharacteristics. A long asymptomaticperiod following initial infection may significantlyincreasethe time to identification &nd th€ time to linking the infection with blood transfusion, Thc American Medical Association (2000,seeChamberland,2002)describedthe historical evolution of transfusion-related transmissionof HCV in the United States.In the 1970s,the risk of HCV infectionwasveryhigh (>1./100). The improvementsin donor scregningand testinghavecombined to resultin substantialdecreases in transfusion-transmitted infectionsduring the I980sand 1990s.On the oth€r hand, other factorsalsocontributeto the incidenceratesoftransfusioir-related infectionsthacmay be reachedsuchas the window period for the emerging pathogen,its incidenceand prevelancein the donor population..,(Chamberland, 2002).Our economic evaluationwas performedfor differentlevels of emergingviral infectionrisk betweenli 100and l/ I00.000transfusions. 22 ス〔ルイὸ″“αtt Ct al Asymprom.tic HIV Cosi-effectivenesof INTERCEPT bloodsystem 23 Table 4. Cost data for diseasestages related to yiral infection Asymptonaac HⅣ Annual cost(C)(SD) E_・ ly symptonatic Hlv* StageA: Asymptomstic StageB: Symptomatic StageC: Aids aョ y sy嵐p10mllc Early syコptOmattc Hepatitis Viral Degativ€ . Acute hepatitisCt Chronic hepatitisI CompensatedcirrhosisI D&omp€nsted cinhosisl Hepato€llular carcinomal Liver transplantdtion,lst ycarl Livertransplantation,' subsequentyarcl ArDS Early sympω、31c HIV inFeclon Go symptomatic LatOり “pl● Inatlc AIDS *D*ock et al (2001),' to@urring ir approiimately (Harbarth et a/., 2000). lwong & Nev€ns (2002). DcaCl ,ate Symp10nlalc A:DS Flg. 3, Structureof subtreerelatedto transfusion-transmitted infection with HIV. Under eachbranch,tbe probability of transitionfrom the lef! to the right h€lth stateis shown.The probabilitics wercobtainedfrom publishedliteralure. (Miners,2001), Impact of tr'ansfusiontansmit ted infections The impacrof transfusion-transmitted viral infections was calculatedby simulatingthe clinicalprogression mtes over differentdiseasestates(Figur€s2 and 3) obtainedfrom literatureand assigningcostsClable4) and utilities to €achstate.Utilities are valuesrepresentingthe quality of life in a certainhealthstatus. Utility valuescan range between0 and I, with 0 representing deathand I represen(ing a stateofperfect hEalth,The time spent in a certain health stat€ is multiplied by the correspondingutility weight to accountfor the quality of life in that particularstate. The Dtility valuesappliedin the modelwereobtained from previouspublishedresearch(Table3). Regarding bacterial inf€ctions,9.770 have been reported fatal and 26.5Yolife threatening(France, Andreu el al.,2002). For the current analysis,non: fatal infeitions werenot attributedany reductionin quality of life given their limited duration. Fatal ot life-threateningbacterialinfectionswereattributeda managementcost derived from previous research showinga tdtal costper sepsis relatedto severesepsis, episodeof €l 7,988(SE = I 145)(Larerreet a\.,2002). Table 3. Utility weights applied for diseasestagesr€lated to viral infection Ullり (95%CI) HIV I ASymptoma●o 094 3)lTengS 02) (CD4>500 odis rnm・ ' C D 4 2 0 5←0 0 c e n s m m ・ 082 CD4く 200 079 AIds 0.77 Hepatils Vlrai negative 1 Chronic Hcpa薔 tis 0 8 2 ( 0 ●■ 9 ) Compcnsatcd CiFrhOSiS 0,78(0,49) D∝ ompenmted Cirrhosis 065(03→ 88) Hepatocellular Carcinoma 025 ol却 ‐ 5) Li“r transplantaton,Ist ycar05(01:つ 7) Finally, the calculation 25% 2300 ‐ 125 250 8060 10,000 50,llllQ 8700 of HCV of indirect transmissions costs incurred infectionsis summarized from transfusion-associated in Table5. Costdata Scenariosevqluated The costsper transfusion of €371.84for SDP and €274 for averageRandom Donor Platelets(RDP) wbreobtainedfrom.officialsotrrces(RIZIV/INAMI, In the basecase scenario, the implementation of the INTERCEPT blood systemis assumedto eiiminate the risk for HIV; HCV, HBV and bacterialinfection. Table5, Methodsfor indirrctcostelcuiations(adults) Productivityloss @lculations Haematologiel cbncer Br€st €nftr CA3G Employedprior to undalying diagnosis* Average z daysper yearactive' Percentresumeactivity post trmtmentt Annual a days lost ifinfetedt Duration of produclivity loss' 48% 218 o/ 70: From month 6 10 end stage$ 39% 167 6'l 44 From month 6 to end stagd 2s% 218 100 uftr cosls Unit cost per hou.(€) 5 years{ 23** Thc same ut"ity values wcre aplucd roF卜 ● C vims as for patRヽ hepaltis B virus rdatcd hcalth statcs(Dushako ′ ′ ′ ,1995) ι CABC. coronary artery bypus graft. rAge and s9x matched natioral data(National Itrstitute for Shtistics, ?001, availabje at \w.srarbel.fgov,b€). tBradley & Bednarek (2002). {The annual nunber of days lost it infected = % active ptevr'ouslyx n working days/year x 70 who would resme agtivity dgspit€ under, lying diseasein the absa@ of inf@tioo (e.g. 48% x L18 x 61yo = 10). {B@ausethe employmrnt ntg applied js basedon calculationsfor the entire aduir populatios up (o all ages,thc age at diagnosisdoeshor neei to be taken into a@una for progmmming duration of ac(ivity. However. durinE the rnd stageol thc underlying dis@se,no prodrctivity iE assumedin th, absn@ of infetion; hence,no productivily loss an be attributed. !l?0% of patients arc undrr 60 year6of agc at the time of inteden(ion. 25% of thes are actilc for aD estimarcdfurther durariot of 5 years. Beyold this duration, no productivity is Numed in lhe absenc. of rnfection; hence, no producliviry lo$ can bc arrributed. r*lncludes di@t wag$ + mployers chargcs(National tnrlit!te for Statisti6, 1996, avaihble ar 'M.sratbel.fBoa.bc) “!:Pubishing Ltdi暉 rr“ "νear,F.16,17-30 ぉl。 0211t16 Blaoお @ 2006Blackwelt Pubtishing Ltd. T,esfusion Medicne, 16, 11-!O ζ :乱 l:撃 ユ 」 躍￨ln, 07o24-0・ 87) ［Ｎ Ｈ D“ ] 2231(1955) 7899(7070) 25,736(20,76o Red'CrossBelgium).Thesecostsincludef-irradiation arid donor screeningtestsexceptNAT. The cost of inactivationusingthe INTERCEPT blood systemis estimatedas €125 per inactivation session,heDceper platelet transfusion.This c6st includesthe costfor the systemitself(€ 90, including VAT) as well as the costsfor ma[erialand personncl to perform the procedure(potential savings at the level of plateletprocessing not taken into account).In the model, the averagerransfusion cost per patientis calculatedconsidering the basic transfuslon cost,thecostof theINTERCEPTblood systemand the averagenumber of transfusionsper patrent, With regard10legalcosts,we assumedan average per bansfusion-associated costof €100,000 infection with HIV or with emergingvirus, based.on law suits or governmentalaction reporisfrom differentcountries,includingBdlgium(Pressconference Minister of PublicHealthBelgium,l9 September 2001,Hof van beroep;Gent,I'kamer,24 April 1998). Althoughfor other infection types, there have been legal procedures startedin Belgium,We.havenot includcd thesecosts in the model, becausenone of the law suits have beenfinalized(someare ongoingfor up to l0 years). 24 K. Moeremanset al. Including prOcessing benertts of INTERCEPT, rcsulting in a tcduccd cost For,la"10t proCessing and tcsting,leads to lower cost‐ cfFectivcncsS ralos CaOIC■)and dohinan∝ Of IN「ERcEPT aheaay at an cmerglng lnfccJo■ rlsk o「 1/1000・ Theや ‖。Wing thresholds oFcmγ ging infecJon isk for thc IN「 ERCEPT system tO become dominantin all indicaJo,sa"。 bservcd DOnlinancc is prcscnt aS frOm an clncrging isk 1/107,tranSfu● o「 Ons■ sce‐ nano l,1/1697●anSfusions in scenaJo 2 and 1/1791 in sccnario 3(Table 9) (costiQALY)scenario Trble6. Costeffstiveness virusor emerging virusl/100,000 | - no emerging DISCUSSION ALL-A _ Thc Objccavc of thお stuly Was tO assess thc cost‐ cffccuVeness oF tht INTERCEPT blood systcmi For this purpose,a health cConOmiq modd was dcvel‐ 9ped, cOmpariig thc bveral outcome in a world with IN「ERCEPT, wherc infectlons bccau`e of blood traisfusions are prevcntcd,to a"orld without INTERcEPT whereinf● ctibns ttay 6ocur Threc sccnarios wcrc dcvclopcd including different levels ofINTERCEPT benctits rrom thc prcventio■ o「 inFeclonS up to hiltiple ccsslng pr● benefIヽ : redun‐ d a n c y o f b aJc ttce」“ r a l s c r c e n i n g‐ tarnad トγ ing,宙 assulllptionS undcrlying odel.wcre the“ that pathOgen inacJvation is 1 000/。 ercct市c and is not associatcd with 7ersl even“The IMERCEPT maiOr or costly ad■ ,9reCning for infccJo,s l thari prcvents thetanSmis‐ jon ofncwlathogcnsbcroic thcyha17ebecn iden119d. RESULTS The cost-effectiveness ratio is highly sensitiveto the risk of infectionwith the emergingpathogenand to the indicationandage group considered. Scenariol: In the absenceofemerging virus, the cost-effectivenbss ranges between 3,459,201€per quality adjusred life year (QALY) to 195,364€l QALY. At the lowestsimulatedrisk of the ernerging pathogencontamination(l/l 00,000),the cosi-e(Tectivenessratios rangebetween3,355,308€/QALYand 165,05t€/QALY,dependingon the underlyingdisease (Iable 6). With increasingrisk of emerging pathogen transmission,the cost:effectiveness ratios steadily decrease(improve), with a maximum of Z,594,l20elQALy at l/10,000and of 223,255at l/1000.(Iable 7) and INTERCEPT beingdominant in the majority of cases,maning cost savingand producingexrraQALYS.Ar l/100, rheINTERCEPT blood systemstrategybecomesdominantin all sases, '点 胤騰 識淵∵幣:II譲 :畷:蝋論器 Absent Pre.lent .Absenl AML-C .lr . Preient Absent Present ALL'C Absent Prcseni NHL.A Absdnt Prgsent NHL-C Abssnt Prescni Cヽ`L Absent Prcsent Absent Present Wlthout INTERCEPT 42フ 9 With INTERCEPT 5915 Withott INTERCEPT 4292 ■lth INTERCEPT 5915 Without INTERCE'T 4277 ヽ Vith INTERCEPT 5915 Without INTERCEPT 4295 With INTERCEPT S915 ヽ Vithout INTERCEPT 4290 With INTERCEPT 59i5 WIthout IN「 ERCEPT 4304 Wih INTERCEPT 591S Without INTERCF_PT 4275 With INTERCEPT 5915 VithoutINTERCEPT 4290 ヽ With NTERCEPT b915 ヽ/ithout INTERCEPT 4502 ヽ Vヽ th rNTERCE'T 6161 Without INTERCEPT 4522 NVtth INTERCEPT 6,61 Without lNTERCEPT 4455 Wlth IN「ERCEPT 6161 Without INTERCEPT 4473 With INTERCEPT 61 61 Without INTERCEPT 3638 With INTERCEPT 4929 Wlthout INTERCEPT 3659 With INTERCEPT 4929 WIthout NTERCEPT 360 With IMERCEPT 493 Without INTERCEPT 361 3 WIh INTERCEPT 49'9 Mar」nd l● ● rC/E EFrlcacy† ettcacy†(lCER)‡ 1・ 99953 200000 199952 200000 0・Ol1047 000048 3199162 3200000 000838 31 99019 32000110 000981 1625 1611 1640 1624 1659 1639 1706 1688 ０ ７ 鸞欄 AML・A V a r 」n a l Cost● cost* 締爵趙 Stratcgy 299929 300000 1 000071 299927 、 3=Ol10110 0 00073 1599602 16.00000 1599562 1600000 000398 000438 3,459,201 3,355,308 195,364 165,051 2,280,181 2,196,998 411,522 370,981 599850 6'00000 599843 600000 0100157 2599302 26100000 2599200 2600o00 000800 210,949 0・00203 636,067 0・ 00216 586“ S9 0:00032 422,784 999797 1000000 999784 1000000 15,99968 1600000 1599967 1600000 000150 000698 1,105,343 1,045,085 24■ 59〕 000033 395,535 implcmentalon Of diagnosic screening tes■ would BRCA Without INTERCEPT 1000 Absent 299984 takc tlmc,during whlch the pathogen can ergce轟 a,d With INTERCEPT '380 300000 000016 2,328,169 “ight catse numOro,s transmisslons WithOut INrrERCEPT 1003 Prestut 2.99983 Historical data on the rlSo of transfusiOn‐ isso・ With INTERCEPT :380 3・ 00000 0.00017 2,285,263 ciatcd infectlons with HCv,HBV and HIV havc shown thitthc●sk can r“ ch vew high lcvelsfore bё A, adltts; ALL, aate lymphoid lcukaemiai AML acuto myeloid leukaemiai C, chjldhood; CABG, @ronary 6ncry bwass gmft; CML, scrcening measures haVc bcen dwcloped For implc‐ chroric mycloid leukaemia; ICER, incremental 6st,effectivqc!$ rario;.NHL, oon'Hodgkin's lymphoma; QALY, quality adjusbd life year. icost and marginal cst in €. mcnt1lon in dO■ o「screening s9hedules Aヽo lEfficacy and malginal efliecy in nunb€r of QALYs. reCClly,thcre has been an epidclnic 9f Wcst Nib cost€Ilecliyetrassin €/QALY gaincd. lMarginal virus in thc Uniteo StatCs,a virus which was shown to bc transmittablc via blood transfusion Thc rlsk of prompt introduction of expensivescreeningteits in 2005). In our siudy, the rate of infection with an transmission thrpugh transfllsion at thc epicentrc of the US transfusionsafety progamme (NAT tests). emergingvirus wassetat differentlevelsrepresenting the epldcmic(1999)has been eslnated as high as onc However,consideringthe time of first det€ctionof differentstagesof emergence. in 3700 to onc in 5555 trans● jons h high‐ ￨“ arCas West Nile virus in .the US.(1999)and the time of In the absenceor at veri low-risk levels of ′,2003).Esimatcd mcan risks in (Hardngton′′α implemBntationof NAT tests in routjne blood emergingvrrus,of <l in 100,00blransfusions, the o ne in 6667 1ot o,,1■ 811 1ona‐ 2002 rangOd fro摯 screening(2002),the'lag time betweenemergenie cost-effectiveness ratios were high in somepopula。 lfr総 was 3 years(Allain et al,, and blood safetymeasures tions, dependingon the underlyingdiseaseand age 器 :ゝ鷺L滞 隻 胤 棚 :設 i講 照犠 ・ 02006●lackw`‖ P“ushiig Ltd,rr“ "MCaic誡 ′ 30 ,lc'フ ψs● O 2006 Blackwcll fublishing Ltd, Tr@tfus@n Mpdtcine,16, 11-30 ＮＮ Ｈ a`on an`reduC● ゛ 。 i br platttt、 ¨tc Two haln Emergl電 Type ︲ ９ Additional processingbenefits(seefurther scenarios) are not consideredin this scenario.Given the evidence,it is clear that a risk of emergingvirusesin the future is existent;however,the timing and levelof risk is unknown. Therefore, the assumption of neither the presenceof viral risk nor the absenceof viral risk gan be supportedas a reflbctionof reality, Therefore,it was decidedto presen! the basgcase scenarioas a double scenario,taking into acoounta similar probability of absenceand presenceof an emergingvirus.To theemergingvirus,differentlevels ofrisk wereattributedbetweenI in 100,000and I in 1000.The highestand lowesi risks are shownin the. first scenarioin TablesI and 2. In the secondand third scenarios,the implementalion of the INTERCEPT blood systemis assumed to eliminatethe risk for HIV, HCV, HBV, bacterialand emergingHCV likd virus, and in addition, a set of processingSenefitsare considered.In scenario2, the elimination of BactAlert testing(corresponding cost and platelet wastereduction),the storagetime irrolongationto 7 days,leadingto 5004decrease in overdue plat€lets wast€, th€ elimination of SDP ALT testing on SDP platelersand the eliminationof .firradiation were assumedto be associatedwith the INTERCEPT blood system.In a third scenario,the following benefitswere assumedin addition to the benefrtsin scenario2: the eliminationof NAT tests and syphilis tests(VDRL) on SDP units-.leading to reducedcosts (NAT costs eliminated).Scenarios2 platel€t proand 3 imply a reductionin the cost for cessingand testing. Cost-effectiveness of INTERCEPT bloodrystem 25 26 Cost-effectivenessof INTERCEPT K, Moeremans et al. Emerging virus AML、 A Absent Prcscht AML‐ C Abspnt Prcsent ALL―A Absent Present ALし C Abscnt Prcsent NHL‐A Absent Presenl Absdnt Absent BRCA Absent Prcsnt WithoutINTERCEPT ヽ Vith INTERCEPT WithOut IN「 ERCEPT ヽ Vith INTERCEPT 4290 5915 5736 5915 31 9916 320000 31 8486 320000 29993 30000 29973 30000 WlthoutINTERCEPT With INTERCEPT WithOut IN「 ERCEPT With INTERCEPT 4275 5915 5781 5915 WithOutINTERCEPT ヽ Vith INTERCEPT lrERCEPT Withollt I● ヽ Vith INTERCEPT 4502 6161 6492 6161 W,thoutINTERCEPT With INTERCEPT WithOutIN rERCEPT With INTERCEPT 4455 6161 6251 6161 ヽ Vithout INTERCEPT With INTERCEPT Wlthout INTERCEPT With INTERCEPT 3638 4929 5791 4929 WithOutINTERcEPT Wlth INTERCEPT ヽ Vithout INTERCEPT Vith INTERCEPT ヽ 360 493 522 493 WithOutINTERCEPT With INTERCEPT ヽ V“houtINTERCEPT With INTERCEPT 1000 1380 1317 1380 1638 -164 1625 179 1640 134 1659 -331 1706 -90 1291 -862 159960 160000 159565 100000 519985 60000 59918 6.ooOo 259930 260000 258903 260000 99980 1 ●0 0 0 0 99845 10.0000 15・ 9997 16 oo00 159979 160000 29998 30000 29997 30000 00o16 223,255 AML C 00084 195,364 0 1514 -1084 ALL A 000o7 00028 2,280,181 164,960 ALL C 00040 00435 411,522 3086 NHL A 00015 : 0 0083 1,105,341 ,40,109 NHL C 00070 0 1097 244591 -817 CML 0.0020 636,067 00155 -55,479 CABG 0 0003 422,784 00021 -14:039 BRCA 010002 00003 2,328,16, 190,448 A, adults; ALL, scute.lymphoid leukacmia'AML, acrtc fryeloid leukaemia; C, childhoodi CABG, coronary artery bypa$ graft; ICER incremmtal @st-cffetivcncss ratio; NHL, non-Hodgkin's lymphona; QALY, qrality sdjusted life year. *Costandmarginalc6t in €. lEffiacy andfrarginalefficacyin numberof QALYs. in €/QALY gaincd. iMarginalcost€ffectivencss group. In children, the results were much more favourable. Considering the cost-effectiveness of other, rec€ntly establish€d interventions in transfusion medicine, the INTERCEPT blbod system compares well with these interventibns, especially taken into ac4ount that only the economic implications of Cost* WihoutINTERcEPT With INTERCEPT Without INTERCEPT ヽ ヽ lth INTERCEPT 4292 5329 4292 5276 1 9995 20000 1 9995 20000 ヽ VithoutINTERCEPT ヽ Vith INTERCEPT Without INTERCEPT With INTERCEPT 4295 5329 4295 5276 ヽ VithOutINTERCEPT With INTERCEPT Without INTERCEPT Wlth INTERCEPT 4304 5329 4304 5276 31 9902 32o000 31 9902 320o00 29993 30000 29993 30000 Without INTERCEPT With INTERCEPT WithOutINTERCEPT With INTERCEPT 4290 5329 4290 5276 159956 160000 15・ 9956 16 0oo0 ヽlthoutrNTERCEPT With INTERCEPT WIthout INTERCEPT Wth INTERCEPr 4522 5552 4522 5496 5,984 60000 59984 Wlthout INTERCEPT With INTERCEPT Without INTERCEPT With INTERCEPT Without INTERCEPT LVlth INTERCEPT WithOutIMERCEPT Wlth INTERCEPT 4473 5552 4473 5496 259920 260000 259920 Without IN「 ERCEPT With INTERCEPT WithOut I卜 『ERCEPT ヽ Vith INTERCEPT WithoutINTERCEPT With INTERCEPT ヽ Vithout INTERCEPT With INTERCEPT 361 444 361 440 3659 4441 3659 4397 1003 1244 1003 1231 Etlicacyl Marglnal MarginJ C/E eFI● a Oy十 (ICER)￨ 00005 ‐ 00005 2,143,435 2,032,6,6 00098 105,389 00098 99,924 00007 1,398,458 00007 1,325,297 00044 00γ 4 237,275 225,028 00o16 6 0 0 0 0,〔0 , 9 1 6 ８ ７ Prcsent 4277 5915 6079 5915 3,459,201 Marginal 6t* Strategy ３ ８ CABG WithoutINTERCEPT With INTERCEPT Without INTERCEPT With INTERCEPT AML A 00o05 Scenario ７ ３ Prcsent 1 9995 20000 1 9985 20000 Type ２ ８ Absent 4279 5915 5568 5915 . Incr C/E (ICER)I 260000 99978 :00000 99978 100000 159997 1600o0 159997 160o00 29998 3 0000 29998 3 0000 00080 1 90o80 656,438 620,812 134,763 127,783 00022 : 00022 340,449 00003 248,647 00003 361,091 235,227 0 0oo2 1,459,408 0 0oo2 1,383,572 A, adults; ALL, acut. lymphoid lskaemia: AML, acute mltloid leukaemia; C, childhood; CABG, coronary arrery bypass grafi; CML, chronic myeloid l€ukaemia;NHL, non,Hodgkin's lyinphoma; QALY, quatity adjustcd life year. "Costandmarginalcostin €. tEfffcacyandmatginalefli@cyin numb€rof QALYs. in €/QALY gained. lMarginalcosFcffectivenN curr€ntly tested pathogens were included, whereas currently not tested pathogens may also induce costs. This result is confirmed.by the results of a previous health economic evaluation of the INTERCEPT system for platelets within the US health care system (Bell et a1.,2003), as well as in d European setting (Postma et al., 2005). For example, NAT tests, recently implemented in rogtine donor-screening prograrrmes in many countries, including Belgium, showed costeffectivenessratios ranging flom €25,000 to €2.3 million per life year gained Ueh et al.,2002). NAT tests for HIV have consistently been associated with costeffectiveness ratios over €l million per' QALY (Jacksoner al.,2003; Marshall et a\.,2004). @2006Blackwell Pubushing Ltd, Trusfusion Mediche,16,11-30 O iOoegtack*,;ltPutlishingLtd, Trwf'bn Medcine,76,11-30 ｍ倒 Ｈ iCML WithoutINTERCEPT With INTERCEPT WithoutINTERCEPT With INTERCEPT Marginal efficacytr ３ ２ Prcsent Effieacyl ９ ７ NHL‐c Marginal cost* Strategy 27 Table8: Cost eflectivenes(cost/QALY) r"un"rio, j and 3 - emergingvirus l/100,000 (cost/QALY) scenarioI - no emergingvirus or emergingvirus l/1000 Tsble 7. Cost effectivcness Typc blood systm Hence, these very high cost-effectiveness ratios have noJ preventedtheseblood safety measuresto be introducedin many countries.When considering also the cost-effectivensss ratios for other interventions to preventaccidentalinjuriesor death such as traflic safety measures;it seemstha! society or at leastauthoritiestendto placea very high valueon 28 K. Moeremans et al. CosFeflectivenessof INTERCEPT : Thresholdemerginginfectidn risk Type S@narioI Senario 2 Scenario3 AMLA AMLC ALL A ALL C NHL A NHL C CML CABG BRCA 1/789 1/1107 895 1プ 1/925 1/1205 1/1057 1/1675 1/1222 1/8,8 1/1230 1/1722 1/1400 1/1439 1/1905 1/1644 12692 1/1932 1/1306 1/1297 1816 1ん 1/1476 1/1510 1/2004 1/1738 1/2858 1/2037 1/1380 Mean 1/1079 1/1697 ■/ 1 7 9 1 A, sdulb; ALL, acutc lymphoid leukaemia; AML, acute myclojd leukaemja; C, childhood; CABG, coronary ariery bypass gafr; CML, chronic hyeloid lcukarmia; ICER, incremental cost-effectivenss ratio; NHL, non-Hodgkin's lymphoma. ACKNOWLEDGEMENTS We thank the following partiesfor providing valu. able informationwith,rEgardto blood safetyand policiesin B€lgium. blood transfusion j Red crossservicesFlanders:Dr L. Muylle o Red crossserviesWallonia:Prof, D. Sontae . HaerhatologyDepartm€nt, University Hospital Ghent:Prof L. Noens ! Hasmatology Deparhnent, University Hospital Gasthuisberg Leuven:Prof M. Boogaerts r.AnaestheSiolory, University Hospital Ghent: Dr L. De Baerdemaeker . Anaesthesiolo$/,OL Vrouw Hospital Aalst: Dr L. Foubert o Centrefor vaccinology, UniversityHospitalGhent: Prof G. Leroux-Roels . HCV patientsorganisation: Mrs Colinet REFERENCES Altain,J.P.,Bianco,C., Blajchman, M.,. Brecher, M., Busch,M., Leiby,D., Lin, L. & Stramer, S. (2005)Can pathogeninaclivation offer protcction agains!the threat of emergingpathogetrsto the blood supply?Transfusion MedicineReviews,19, I l0-t26. Amotosalen Allogeneic ellular iffiu$otherapy system (2003) INTERCEPT Plasma Syst€m, INTERCE?T Platel€tSystem,559. EioDrugs,t7(l), 6G68. Andreu, G., Mbrel, P., Foresticr,F., Debeir,J.; Rebibo,D., Janvier,G. & Herv6,P. (2002)Hemovigilancenetworkin FraDer organisation and analysisof imcdiate transfusion incident reports from I994 to 1998. Transfusioit42, t35ilt364. Bell, C.E., BottemaD,M.F., Gao, X., Weissfeld,J.L., Postma,M.J., Pashos,C.L., Triulzi,D. & Staginnus, U. (2003)Cost-effectjveness of transfusionof platelet components preparedwith pathogeninaclivation treatment (9), 2464-2486. in the US. Clinical Therupeutics,.2S Biggerstaff,B.J. & Petersen,R.P. (2003)Estimaredrisk of the WestNile Virus through blood transfusionin the US, 2002. Traufusion, 43, I 007-I 0 I 7. @ 2006Blackwcll Publishing Ltd, Translutton Me.ti.ine,16,17-30 (1995) Elmaagacli, A.H., Basoglu,S., Prccny,R., Trenschel,R., Ottinger,H., Lollert, A., Runde,V., Grosse.WildgH., Beelen,D,W. & Schaefer,U.W, (2002)lmproved disease. fre-survival aft€r lransplantation of peripheral blood stem cells as compared with bone marrow from HLAidentisl unrelateddonorsin patientswith first chronic phasechronicmyetoidleukemia.Blood,9 (4), I I 30-l 135. Engolfriet,C;P., Reesink,H.W., Klein, H.G., AuBuchon, J.P.,Strauss,R.C., Kruius, T., Maki, T., Rebulla,P., Hogman,C.F., Knutson,F., Letowska,M., Dickmeiss,E., Winter, M.. Henn,G.i Menichetti,E., Mayr, W.R., c鰍 恥叩qQ i 獣札 … 頭 ι 跡 4 Q い “ は Flanagan,P., Manin-Vega,C., Massuet,L., Wendel,S., Turek, P., Lin, C,K. & Shirato T: (2003)The future use of pathogcninactivatedplateletmnentrztes. Vox sDguinir, 85, 5+.66. Farquhar, C.. Basser,R., Hetrick, S., Lethaby, A. & Marjoribanks; J. (2003) High dosc chemotberapyand autologous bone marrow or stem ell kansplantation versus@nventionalchmotherapy for womenwith metastatic breast caner. Coihrane Datab8e o/ Systematic they pose ak iふ to the satty 6f traiSfused blood Reviews. and l, CD003142. blood pr9duCt,7α "￨“ ′力 をε′ わり つお″ α∫ り,34,797-805 Gziev, D., Galimberti, M., Polchi, P., Angeluci; E,, ,v,vcCo101gh,TI&Dayah,A p 12001) Giardini, C., Baronciani, D., Andreani, M., Persini, B.r 9araVin。 Erq, 8.. Sodani,P.,Manna, M., Nicolini,G., Visani,G., Luerelli,.G.; AIEOP (2002) Fate of chronic myeloid leukemiapatients treat€d with allogeneicbone marrow transplanlationor chcmotherapyand/or interferon at a singleenter: long-termresults.BoneMarrow Trmplant, 29(1), l-.8. Gordon,S.C.,Bayati,N. & Silveman,A.L, (1998)Clinical genou,lcuketta aFter ealy,an,plaitatlon o「 pheno‐ typlc■ d or outcomc of hcpatitis C as a functiof, of mode of trans. ″ matChed bon9,arrow i。“ rc●tё mission. Hepatology 28 (2), 562-567, Grass, J.A., Hei, J.D., Metchette,K., Cimino, G.D., DccoOk,R,De16。 'α'(2001) Wiesehahn,G,P., Corash, L. & Lin, L. (1998) ■6r,A.M,0,Craeve,D,´ Dicct cost Of‐ hcall care fOr● IVIAIDS palcnts ii Inactivationof leukocytesin plateletconwntratesby Bclgium ′ /,sc″ 1113(6),721-731(abstract) photochmiml treatment with psoralen plus UVA. D i n l , G i C a n c C d d a , R , L o c a t a b:,AF,"pBaon● Blood,9l,2l80-2188. d i ,■G っ A l c c s a n d6Ⅲ , L p : , P O r t a , F , U d O,rcz,。 Harbarth, S., Sacs, T., Berger,'K., €, cl. (2000)The eaMCSSlna,c, se,W,Marcn∞ nomic burden of hspaiitis B in Qermany, Eur J ,P,Fanin,R,Falda,M, 和 LioH,F:,Ar∝ Epidemlol,16 (2), I 73-l 77 (abstract). Harrington,T., Kuehnert,M., Kamel,H., Lanciotti,R.S., L a m p a rie,‖ T , G l o r g l a n t G ",LEa"nMiann。 z l t t i , C Hand, S., Cunier, M., Chamberland,M,E.; Pelersen, &Baclgalupo,A ror ihc cITMO(2001)U● relatcd L.R. & Marhn, A.A. (2003) West Nile Virus intection ・ d o n o r p a r r o w t r a n s p l a n t a t i o n : a n u p d a ttransmitted e o f t hby e blood c x p c itransfusion. ‐ Trarcfusion, 43, e,cc 6r the ltabai pOne Marrow iransplant CrOup I 0t 8-t 022. ゎgた,,86,451456 (GITMO)Irae″ὰο Hu, K.Q. & Tong, M,J. (1999)The long.tem outcomesof Drcsse, MIF,Boogaerts,M"Vcnnylen,C,Nocns,L, paticntswith compensatedhepatitisC virus-relatedcirrFoFant,A,Schots,R,Doyen,C,BIoh,D,3cmernan, hosis and history of parenteralexprcsurein the United Stales.Hepatology,29 (4), l3l l-1316. Jackson,B.R., Busch,M.P., Stramer,S.L. & AuBuchon. cxpcHencc in unrcllted dOnOr bone marrowsplanta‐ traり J.P.(2003)The cost.effectivenssofNAT for HIV, HCV, .6on:idcnditttOn Of∝n■r OxpCience as al impprtant and HBV in whole.blooddonations.Transfusion,4S (6), 't2t-729. m″ο 々 lCat 84,637ヽ 42 r∫ rぁれ a,リ u 面t 口ヽs e d b y N ^ T .ゥ 43,H73-1174 Bぬ̈ lム 闇漱Ⅱ 乳明 棚 潮{織出:糧 cX16:A,Com‖ :階 :,Mi 憩 ,M"省 ■ti9駐 y識:IL驚 弊 棚 ‖ 寵:轟t島 Tttg亀 uじ ′ 撃 謝 勝 魔槻肌ソ き ぷ り 腸り ず 観 塁駿1's紺 監:ヒ 現 冒i満轟r織よ 驚: 盤需胤 謂滞棚l後 譜 鮮 肥lWさ :l[ l課 躙 li鑑 蹴 搬 器 棚嚇 鵬 0め c漱な E口 e● “ …″ 凛 s｀ お 濫秘 。 鴨iた 話 i慾 鸞,1嶽 湛鱗T'∴ ⅣP 珈 :網 : 戦 l轟F器 ぶ 酬 =f詣 ° た ″ツ′ グ 省 H0 l躍舞》1警(lγヤ 等争 υ 驚げL}::LAi:,TI VitLIttλ Fぽ 蹴ふ電 蹴:し FI身 漢 器∬ 11常鶴語 prognoslc factor H“ な 02006馴 ,c取引PubLs,ng Lta rraψ ル,16,17-30 ,レ 雄 ″ε ヾＮ ［ measuresto reddceunintentionaldeathsand injuries by Yeh $eh et a1.,2002),Therefore,it wassuggested et al., (m07) that transfusionsafetymeasuresshould evaluated be usingcost-effectiveness thresholdsthat are higher than those typically used by healthcare decision makers,reflecting.the higher value placed on suchtypesofinterventions,whereit. is considered lunfair' ifpatients haveno accessto the bestpossible protection ffeh et a1,,2002), Also the cost-effectiveness analysesshould take into accbuntall p_o-tential benefitsof a newintervention such as processingbenefits,indirect costs from productivity loss(Yeh et al.,2002). When a morepro-activeviewpointis taken,from a public healthper'spective, the apparentrisk for emer' ging virusesshouldbe taken into account.At emerging viral risksbeyondl/1000 to l/2300transfusions, the INTERCEPTslrategybecomes dominant,that is savingmoneyand producinghealthgains. In conclusion,consideringthe apparentlyapplied thresholds for cst-effectivenessin the field of blood transfusions,the implementarion of .theINTERCEPT blood syslemcan beconsidered cost-effective and even a dominant strategytakinginto accountthe potential of a newpathogenin the future. risk of emergence 29 Dusheiko,G. & RobertsJ. Treatmentof chronic ・ m甲 ° ・ tt° ° “ type B and C hepatitiswith interf,eronq: an economical 'H '7SIⅢ 11り 糧 Tl総,・ "lcVI喘remiaνin HCv infCCtiOus appraisal.Hepatology,22, 1863-1873. Busch,M Pi(2003)VcryI。 BrallCy,C J tt Bednarek,H.L 12002)Emplbyment pat= Table 9. Threshold valuesemcrgingvirus risk for INTERCEFI dominane blood system TRANSFUS10N 00MPL101T10NS 3O K. Moeremarc et al. Laperche,S., Morel,.P.,Deschassux,M., Bouchardeau,F., Alimardani,G., Guillaumc,N., Rouger,P. & Lefrdre,J.J. (2003)HtV antibodyscreening remainsindispensable for ensuringviral safetyof blood componentsdespiteNAT implemcntation.Trarcfusion,43, | 428-1432. hten€, P.F., Mocremam,K., Gitis, P. & Annemans.(2002) Sewre sepsis:clinical lrial wrsus daily practie. A @st analysisin Belgum. Valuein Health,5 (6), 561-562. Un, L., Cook, D.N., Wie*hahn, G.P., Alfonso, .R., Behman, B., Cimino,G,D., Corten,L., Damonte,P.8., Dikeman,R., Dupuis, K., Fang,Y.M., Hanson,C.V., Hearst, J;E,, Lin, C.Y., Londe, H.F., Metchette,K., Nerio,A.T., Pu, J.T., Rsme, A.A., Rheinschmidt, M., Tessman,J., Isaacs,S.T., Wollowitz, S. & Corash,L. (l 997)Photochemicalinactivationof virusesand bacteria in platelet conentrates by use of a novel psoralenand fong.wavelength ultravioletlight. Trwfus ion, 37, 423435. Marshall,D.A., Kleinman,S.H.,Wong,J.8., AuBuchon,J.P., Grima, D.T., Kulin, N.A. & Weinstein,M.C. (2004) Cost-eflectiveness of nucleicacid tqt screeningofvolunteer blood donations for hepatitis B; hepatitis C and human imunodefici€ncy virus in the United States. Zox Sanguinis,86 (l), 28-40. Marteffi,M., Gherlinzoni,F., De Renzo,A., Zinzani,P.L., De Vivo, A., Cantonetti,M., Falini,8., Storti, S., Meloni, G., Rizzo, M., Molinari, A.L., Lauria, F., Moretti, L., Lauta, V.M., Mazu. P., Pescamona,L., Pileri,S., Mandelli,F. & Tura, S. (2003)Early autologous stem €ll transplantationversusconventional chemothcrapy as front Unetberapy in high risk aggressive non Hodgkin lymphoma. An Italian Multicenter Randomised Tial. Jownal of Clihical Oncology, Zl, t25s-1262. Miners, A.H,, Sabiq, C.A., Trueman, P., Youle, M., Mocroft, A., Johnson, M. & Beck, E.J. (2001) Asessing thc @st-effetivenessof highly active antiretrovinl therapy for adults with HIV in England. H.f/ Medicine,.2,52-58. Pereira,A. & San4 C. (2000) A modet of the heatth and e@nomicimpact of post transfusionhepatitis C: applioation of cost-effectiveness analysisof further expansion of HCV screening prot@ols. Trarcfusion, 40 (lO), I 182-ll9l. Pigneux,A,, Tanguy, M.L., Mjchallet, M., Jouet, J.P., Kuentz, M., Vernant, J.P., Milpied, N., Ifrah, N., . Cahn,J.Y., Gratems,N., Reman,O., Cure, H.; Caillot, D. & Witz, F., Pillier.Lorietre, C., Tron, p., Reiffers, J. & Soci€ti Francaisede Greffe de Moelle. (2002)Pfior tr€arment with alpha interferon does noi adverselyaffect thc outcomeof allogeneic transplantatjonfor chronicmye. foid feukaemia.BritishJournal of Haenatology, 116(l), r93-201. Postma,M.J., van Hulst, M., De Wolf, J.T.M. & Botteman. M., Staginnus,U: (2005)Cost-effectiveness of pathogen inactivationfor platelettransfusionsin the Netherlands. Trcnslwion Medicine,15 (5), 319-387. Radich,J.P,, Gooley,T., Bensinger,W., Chauncey,T., ' Clift, R., Flowers,M., Martin; P., Slattery,J., Sultan,D. & Appelbaum,F.R. (2003) HlA-matched related hae' matopoetic @ll tratrsplantationfor CML chronic phase usinga targetedbusulfanand cyclofosfamidepreparative reg1men. Blood,t02 (1),3l-35. Seveni!,B., Meral, A., Ozkan,T.,6zuysal, S. & Sinirtas, M. (2003)Increasedrjsk of chronic hcpatitisin childlen with qner. Med PediatrOncol40, 104-110. Soci€, G., Stone,J., Wingard, J,, Weisdqrf, D., Henstee" Downey, P., Bredson, C., Cahn, J.Y., Passweg,J., Rowlings,P.A.,Schouten, H., Kolb, H.J.,Klein,J., BenderG6tze,C., Camitra,8., Godder.K., Horowirz,M. & wayne, A. for thclaleeffsts working@mitte of theintemational bonemarow transplantregistry.(1999)Long tem suruival andlatedeathsafGrallogcneic bonema[ow transplantation. TheNewEnghndJourrulof Medicire,!4| (l), l+21. Taggart, D., D'Amico, R. & Altman, D. (2001)Effecr of arterialrevasillarisation on survival:a systematic review of studiesomparing bilateral and singleintemal mam, mary arteris. L{ncer, 358, 87S-875. Tong M,, El-Farra,N., Reikcs,A., er a/. (1995)Cljnical out@m€s after transfusion-associatedhepatitis C. N Engl J Med,132, 1461-1466. Weintmub, W., Clem€nts, S., Van-Thomas Cds@, L,, Guyton. R., Craver,J., Jones,E. & Hatcher,C. (2003) Twenty-ycarsurvival after coronary artery surgery.An institutioral persp@rive from Emory University. Cir culation, 107, 127l-12'l'7. Wong, J.B, & Nevens, F. (2002) Cost-effectivenssof peginterferon alfa-2bplus ribavirin ompared to interferon alfa-2bas initial rreatment of chronic hepatitisio Belgiufi . A ctq g6 rr oenl:er ol, 65, l -2 (extendedabstract). Yeh, J.M., Bolteman,M. & Pashos,C.L (2002)Economis of transfusioq, Infusion Therapy and Transfusion Medicine,29.218-225. @ 2006 Blackwell Publishing Ltd, Ttawlusion Medicine,16, 17-30 The cost-effectivenessof pathogen reduction technology as , assessedusing a multiple risk reduction model Brian Custer, Maria Agapova, and Rebecca Haulir Martinez BACKGROUND:Pahogen reductiontebhnology(PBT) lor labilebloodcomponontshas lhe potentialto reduc€ lhe risk ol many advaFo €ventsassociatedwilh irans. tusion,Becauseot lhe polentialbroad-spectrum risk reduclloncapabllilyof PFIT,the health.economicsot PRT could bs an importantconsids(alionin decislon makinglor this technblogy. STUDYDESIGNAND METHODS:Decislonanalytic modelscompadngcutrontblood salety screensand inleruentlons to riboflavln-bassd whole blood PRT (currenlly in developmenl)and sepactely to plalelets (PLTs)-and.plasma PFT from thg healthcar€ system perspectivsin Cariadawere us€dlo assosslhe coslutilityof PRT in roducinglhe lollowingadverseevenls: humanimmunodeticiency virus,hepatltisB virus, hepalilis C virus,humanT-lymphotropic vlrus,syphilis,Wesl Nile virus,bactorlarChikungunyavirus,cytomegalovirus, Trypan@oma cruzLg€tl.ve6us-hosl dlsease, febrilenonhemoMictransfusionreacllons,and lransfusion-felatsd lmmunomodulation. PBT was modeledas sn addilionto ratherthan a r8placemsnttor cur€nt intgryenlions. Tha potentlalof PRT to redu6 the risk ot an-unknom paihogenwas nol assesssd, RESULTS:Whol€blood PRT was estimatedto have a cost-ellectivmessot $1,276,000/quality-adjusted liteyear (OALY;96./6contidencelntsrval[Cl] approxlmation, 600,O0O-3,313,000) comparedto currentscreens and interyentlons. PLTs-and-plasma PRT was estimated lo have a @sl€tlectlvenessot 91,423,000/QALY (95% Cl approximation, 8il4,OOO-2,818.000) on an alllranstusionsbgsis. CONCLUSTONS: Bocauseof the complexityof transfuslon risksand prastlces,the cosl.ellecliveness ol whole bloodoI PLTs-and-plasma PRT can be modeledprovidsd that a$umptlons and simplitications are made. Uncertajntyremalnswith respeclto the risk reduction lhal can be achlsvsdtor some advarseevenls,Never. theless,ths rssultsof this cost-eifectfueness analysls €n be used to IntormpolicydecjsionsregardingPRT lechnologyIn th6 contextot other initiailvesdesignedto improv€ transfuElon safety. . wo methods for pathogen reduction technology (PRT),also known m padlogen inactivation, use a photoactive compound (riboflavin or amotosalen) md ultmviolet {UV) light teatment to prevdnt DNA or RNA replication, These methods are being adopted for !he treatrnent of platelets (PLTs)or plasma in some Europeari'countries. Consensus statements from the panel of the Canadian Consensus Conference on Pathogenlnactivationin 2007and summary statements, such as from one of the 2008 US Advisory Committee on Blood Safety and A%ilability meetings, indicate that eco' nomic evaluations of PRT should be conducted and included as part of the information used for making implementation decisions.Ir Previous economic malyses of photoactive compomd/UV light PRT focused on human immmodeficiency virus (HIV), hepatitis B virusS (HBV), hepatitis c virus iUcv), human T-lymphotroplcCl virus (ffTLV), and bacteda.3-6These malyses assumedthatthe treatment process i9 100% effective (residual risk of these Fathogens is eliminated in PRT-treated PLTs) and reported results for specific patient populations Iikely to receive-suchtrmsfusions. The likelihood that these same patients would receive unueated red blood cells (RBCs) and/or plasmatrmsfusionswas not addressed.Moreover, while analyses restricted ro specific patient popularions ABBREVIATIONS: FNHTR(s) = febrile nonhemolytic trustu" sion reacrion(s); PRT = pathogen reduction technology; QALY = quality-adjusted llfe.yed; TRIM = rrostusion-relared immunomodulation; WNV = W6r Nile Wus. From Bldod Systems Research Institute,.San Fmcisco, Califonia; the Phamaceutical Outcomes Resealch and policy Program, Universiry of wdhingron, Seattle, Washingtoni ed Cambridge, Mssachusetts. AUr6s reprint requet s toi Brian Clste! Blood Systems .. R6ercb Instituie, 2?0 Masanlc Avenue, Se FEncis@, CA '941 18; e-mail; [email protected]. Hflird Universiry -Receivedfor.ptrblication May 7, 2OO9;re\4sion recelred March 19, 2olo, and a@epred Mdch 20, 20t0. doi: I0.l I I I /j. 1537-2995.2010.02704r . .TqANSFUSION 20t0is0i246t.2473. Volume50, Novemb€r2010 InANSFUSION 2461 COST‐EFFECT:VENESS OF PRT CuSTER ET AL. based on trmsfusion indication ile informative for assessingwho is most likely to benefit,7they do not help blood safety decision makers faced with selecting interveDlions to enhmce ihe safety of components intended for.all transfusion recipients. We developed a new health economics model to assess the cost-effectiveness of riboflavin-based PRT (Mirasol PRT system, CuidianBCl, Lakewood, CO) in mitigating the risk of transfusion-associated infectious md some noninfectious threats,The first model examines the cost-effectiveness of a technology in development, whole blood PhT,6To model the technology that is curently available in some settings, PlTs-and-plasma PRT, we modified the whole blood PRT model, incorporating data on PUI prcparation procedures and uansfused components to adiust the risk reduction achieved. diseaseoccutrence,butcomes, and costs come from published literature specifc to Canada,When data were not available for a specific diseaseor condition; we used data ftom other countries with preference for US data when available.In accord witi the recommendations of the US Panel on Cost-effectiveness in Health and Medicine, future costs and effects are discounted at 3% per yeurr'r'z andwereallowedtovaryindependendybetween I and5% in sensitivity ana.lysis. We constructed the model and perforrned malyses using computer sDftware (TreeAge Pro 2009,TreeAgeSoftwile, Inc,, WillianstoM, MA). Aspects of the model not covered in deta.i.lunder Materia.lsand Methods, such as amual mortality probabiiities and disease-specificmodels and variable values, are provided as an electronicTechnicalAppendix (avallable as supponing information in the ori'lineversion ofthis paper); MATERIALSAND METHODS Overview Structure of the model The models simulate the costs and consequengesof the following infectlous and noninfectious adverse events: Hry, HBV HCV HTLV syphilis,WestNilevirus (WNV), bacteria Chikungunya virus, cytomega.lovirus (CMV), fi.ypa. nosom crwi, graft-versus-host disease (GVHD), febrile nonhemolytic transfusion reacuons (FNHTX), and trmsfusion-related immunomoiiulation (TRiM). Eoth the set of and the prevalence of adverse events included in each version of the model cm be adjusted to reflect setting-specific epidemiology or disease.In this analysis we neither included an mknom, emerging pathogen nor re$ospectively included a scenario for HIV or HCV when either virus had the highest preva.lencein blood donors. Our reason fornot includingthese pathogens or scenarios is ihat it is relalively easy to construct a set of outcomes with a disease burden profile that is favorable to PRT. However, such a scenailo in the context of $ying to address or mitigate cuirent risks could cloud the assess. ment of the ef6cjency of PRT. We analyzed the cost-utility of PRT for Canada. Canada represent$ an appropriate country for such an analysis because tiere re I) nationally representatiw health care data, ?) active hemovigilmce and trmsfusion suweillmce systemsin some Provinces,and 3) interest in implementation of PRT.Similar to othe! economic analyses in blood safety, this malysis is ftom the health care system perepective and costs aelimited to the costs ofthe safety interventions and the dkect medical costs associated with infections or other adverseevents.eThe results reponed here do not include the cost of lost producrivity or related lnduect costs incurred because of transfusionassociated adveFe events.We used 2007 as the analysis yeu, so all monetaryvalues are adjustedto 2007 Canadian dollars using the health md personal care component of the Canada consumer price index.ro Data souces for 246i1 TBANSFUSION Volume50, November2010 The model has a decision analytic format and is a cohort simulation with separate diseree-specific Maikov submodels to back the progession of each adverse event. Each version of the model conslsts of four sections.The first section is a two-armed decision tree: current scrcens and interyentions .compared with PRT added to currcnt screens,The second section is focused on two charactelistics of blood recipients that influence the likelihood of suwival: age at uansfusion and immuocompetence. The model can be run using surviva.ldata for three agegroups: l) an overall goup that reflectsthe age distribution ofthe entire transfused population, 2) persons 0 to 39 years of age, and 3) persons 40 years or older. These categories were def,ned based on availablepostuansfusion datd that indicate that the probability of swival ls similar withih these latter two broad ege categories.r3't5 The population of blood recipients is also separated i4to those with and without underlyiri immunocompromise, because a subset of the population requiring transfusion may b€ immunocornpronised due to a medical condition, such as cancer,organ uansplantation, or specific infections like HM T[ese patients may be at increased dsk fo! more severeadvene outcomes from transfusion.16Estimates of the size of the irnmuocompromised subpopulation are not available for Canada. Data from the National Blood Service in the United Kingdbm suggest that as majly as 5090 of blood recipien$ ue lmmunocompromised to some degree,with 25% having moderatb or severeimmunocompromise.rT We included immunocompromise in our malysis by assumingthat 2570ofthe transfusedpopulation hm underlying irnmunocompromise. In the model tiis patient goup is at increased risk of monality and faster disease progression, which we included:as 509o incleased postuansfusion mortality in the first yeil after fiansfusion, and increased risi of morbidity from each adverse event. TABLE 1. Percsntageol patlenls lecelvlng lranstuslons by componenl combinatior trom Brltish Columbld 8nd Yukon trsnstusion rgglslry data and assumed riak reduction 8chleved In the PLTs-and-Dlsme PRT model n": : Translosed ib● i¨● mp● comЫhalbns`or 2∞ 7 . 184,842 compOnent) (n・ ABCl onlソ Pocen● ge aavlng eaCh,pe of Ю a COmponent 75 7 Plasma・ c● ntaining tFnslusiolls 99 None ｀ 00 Mは ‐ 還‐ S・ 驚騨「 冒 認llttasm:品 :朧 ) ::83 PLT coltahing,7an8fuSiOns 14 4 i鰈 鼈 sド Assu""P3Tわ duO On a■ u゛menl ractOr(PRT^F), plaima. Components are not assujhed to come from the same blood donor and so carry the independent risk of each adverse event, but the adverse risks for each component would be mitigated in a single inactivation ifwhole blood PRT beconres available. The number of cansfusjons.received in an episode has not been modeled. A.lthough the risk of spectfic infectious agents and of noninfeitious huards varies according to the type of blood component transfused, component-speciflc residual risks are mosdy unreported and are not included in the whole blood PRT analysis. ::‰ Mlxed :諄l'F T A B L E 2 B b o d s a f e t yo ● hs t ea rn vd● e● 3n1■ m e d o●s t s Per donalion @sl Cosl elom€nt CurOnt Screen3 ‐ HIV antlbody HIV NAF HCV OいOb●dy: HCV NAT HBV surace anlgen HBV core an“body , VVNV NAT Rmgstor sonsinvity ahalvsls _ ` HTLVOハD antbOdy SbrObglo lest rr● syp"lls Tola1 44 0o 33 00・ 5500 Bactelal cuture Bacterほ culture' 2500 1875‐ 3125 arter diverslon ‐ 1288 CMV anlbody 10 00 7 72‐ 500 375・ 625 Gamma“ radiat on. : PRT l∞ 00 7500‐ 12500 The third section of the model differentiates recipi. ents into three grcups based on the t)?e ofblood components received. Published data consistendy show that recipientsofPLTSoi plasmaalone or in combination wiIh RBCshave redgced long-term suryival compared to RBConJy recipients,lsreData on the percentageof transfusion episodes that include each blood component type were provided by the Bdtish Columbia Prcvincial Blood Coor'dinating Of6ce for the year 2007 (Table1). We assumed that the component combinations transfused in British Columbia md Yukon are representadveof rhose for the endre country.We aajucted the mortality probabi.litles for PLI recipients and si,paratelyfor plasma recipients using clata published byWallis md iolleagues.r'g The fourth section ofthe model addressestransfusion outcomes thlough detailed accounting of disease and adverseevent progression md costs.Details of how each adverse event is modeled are prol'ided in the Technical lppendix In the model edch trmsfusion recipient is assumed to experience a single transfusion episode consisting of I unit ofwhole blood or the equivalent as RBCS,PLfs, and Ettectlveness ot PBT Curreut blood safety interyentionF used in Canada de listed (Table 2). In tNs analysis, we assumed that all of these interyentions would continue md that unlvercal leukoreduction would, con'at tinue. fhe effectiveness of PRT reducing the risk of each Eansfusionassociatedadverse erent is dependent on the inteNentions already in place,tQ the likelihood of adverse event occur- N rence, and the pathogen-specific per- r'-l formance of riboflavin-based PRT Actual estimates of the efectivenels of PRTunder conditions of normal usewill only be availableafter sufficient posthalketing surveillance data have accumulated. To project the effectivenessof PRT we assumed pathogen-specific risk ieduction factors (Table3). Risk without PRT is 6ased on the observed frequenry of the event, the leld of screening, or estimated residual.risk given current safety measures.Forexample, ihe current estimated residual risk of HBV infection is-l per 153,000transfusiols.2o Good animal models to demonsuate a specific Ievel ofpathogen inactivation for HBV tre not available. Studies of riboflavin-based PRT have.shown that it can successfully prevent pol].merase chain reaction amplification of HBV at concenBatioDsup tD 29,4OOgeql mL.2rWe assumedthat ihe risk reduction achieved by PRT would be l0-fold greater t}lan current testing (hepatitis B surface mtigen and anti-hepatitis B core antigen) givlng an. estlnated residual risk after use ofPRT of I per 1,530,000. Costs The cost of cunent scieens md interyentions applted to every donation in total sum to $44.00 per donation (Table 2). No serologic lntewention for I cruziwas used in Volumo 50,NOvomb● :2010 TRANSFuSiON 2461 CuSTER ET AL CuSTER ET AL. Ｌ ●Ｏ ｅ Ｓ ｃ ８ ｏ０８ ９ ト ５ ■ ５ ｏそ ＾ 慧 ． ＯＳ 一 劇 ヽ も ０■災︶ ０８舌０マヽ︶ ８ エ ． ｏ， ヽ一 ５五一 ５ ８ ｑ ８ ０ ８ ６． く， こ ｇ ８０ ９ ０ ヽ 一 ８ りヽ § 〇ｒ０ ■“● 一 こ超 ，９ じ 〓出 ８ 程§ ８ こ︶ 娑 ８ ８ ８． ８， こ ︸ ヽお０ 〓Ｓに ０ 〇５ 望 § ． ｃｏ一 ３ ． Ｓ︸ ５■Ｅ３イ Ｅ 五ＥＲあく らうち 多 ヽ ｃｅ β ヨ そ ヽ ” も 〓ギ ＲＯ り ８ 魚Ｅ ９ ８ ヒこ ﹄ ｐ ﹂ ♂” お︶０一 ︵ ０し り︸ ３ Ｔ， 奮 ３８ し ＯＮ ●■９ ｏ一 Ｃ ●” ６一 ヽ ︵ Ｐ お︶９ ０ＴＣ Ｏ一 ６一 お︶０” ︵ Ｒ ヽＲ し Ｎ お０， ３ こ 劇 ︵ 澪 Ｐ ，３ 一 ︵ ３ 二 ０こ ８ TABLE4. Cost8 and etlscts ot currsnt Int€rventlons, wtth PFT 6nd incremsnlal coal-sftsctlveness of PFT by transluslon recloient sqe orouo tor whole btood PRT ' , _ Tolal costs for curonl &rgseiinteNentions ($cAD\ (OALY) Efiocts wiih cunent scr€eng4nleryentions Tgtal cost {or PRT adoptlon (SCAD} Eftectswith PBT adoplion (OALY) Incrementalcost of PRT ($cAo) Incromentaleftecdv€ns$ of PRT (QALY) Increm€ntalcost€fI6ctlwh€solPBT($CAD/OALY) (9570Cl approximation) 一 ヽＮ 諄 ０ ´ ５ ●０ ¨ ● る 漏こ ● ＞ ２ヽ， ，こ Ｆ ≧〓 ●■■ゝ ∽ ＞ ●エ ＞０ エ ＞〓 ０ ０ 工， ０ こ 一 き “トヤ一 ２Ｅ ０ ８ ｃ８ ■８ ﹂ ２こ ■ ３ ８ Both one-way ald probabilistic sensitivity analyseswere conducted. All sensitivity malyses were performed using $re overall (a[ ags) blood recipient popuJadon,agespecific sensitivity anallres were not conducted. In oneway ana.lysis,the influence ofa single model.variableover the likely range of possible valugs fo! that vsiable is assessedwith respect to its impact on cost-effectivenes. The one-way analyseshave been aggregatedinto tornado diagrams, one for the whole blood version of the model and one for the Plls-and-plasma model, showing the decreasinginfluence of model mriables. The top tS.most influentia.lvariabldsspecific to each model ae included in each tornado diagrm. Uncenain vuiable values md assumptions such as the residual lisk of each adverse event, PRT risk reduction factors, and tieatment costs werevaried by:50% ofthe baseline esiinate, Tlie costsof blood safety inteNentions including PRT md amual postEansfuslon mdrtalitywere varied by t2570 indicating a477 7.a85246 158.30 7.885335 113.53 O.OOOO89 $1,276.000. (600,000-3,313,000) C6ts and €(€ct6 l-tosg@ 44.92 19.550197 158.3'1 19.550463 113.40 0.000266 . $426,000 . (197,000-1,173,000) 44,76 7.3t1080 158.30 7.311161 113.54 O,OOO08I $1,405,000 (653,000.3;693,000) E probabillty of baclerial contam,: 0.00003 to 0,00001 E mortatlry probabltity ln year ot trandfuslon: 0.10 to 0,30 S cost of PRT per donatlon: 75 to 125 Z probabltiiy of sepsls death, immunocompetent.: 0,5 to 0,3 El dlscount rats for €ffects: 0.01 to O;05 m QoL welght in ysaF tollowlng transfusion: 0.99 to 0.86 S QoL relght tor consequencesof sepsls: 0.59 to 0.79 iE component use adjustmenl taclor for PRT: 1.0 to 1.20 N annual mor,tallty after trsnsfuslon: - to +25% I component specific mortality 8en€ltlvity analysis: O to 1.5 D probabliiiy of T cruzl: 0.OO0OO75 to 0,0000025 X PRT adlustmenl tactor for FNHTR: Z.Sg to l:Ot E probablllg of death In acute T, cruzl stata: 0.03 to o.0ol E dlsutility welght for FNHTR:0.02 to 0.005 N PRT adiustm€nt factor for bactsrla: 90 to 10 A probability of FNHTR:0.002to 0.00057 E probabllity of PLT8 transfuslon: 0,094to 0,194 I Incremental Sensitivlty analysis Overati(altCges)- nesuttsetegory dosUEffectiveness Fi8, l. Tornado dlcgtq QoL welght for tnnsfuaed patient: 0,99 to 0.81 ($mllllons/QALY) shos'lng the range of values used ud resulr6 froh one-wsy sen"ldvity ualyels of the nosr lnfluentlal wl. b6r Ellacts tlre f ug€ of adiacent valus llsted on the rlghl Ruge6 @ prcp'lth the left atrd rlghr ends ofeach horlzotrral baL QoL - quallty of ltfs. vided from low to hlth ot high to low In corcspondene ablo in Oe whote blpod PRT model, Ecch horlantal severa.lof the factors.related to FNHTR, such as the probability of FNHTRs [attdbutable to residual white blood cells (WBCsI evln in leukoreduced blood) and the assumed risk reduction, de influential in the whole blood PRT model. Evidence of the effrcacy of UV light and photoactjve compoud PRT to reduce the occur. rence of FNHTRs continues to emerge; both riboflavinbased md amotosalen-basedPRT have demonstrated a decreasein these adverseevents duing active hemovigilance s$ditls.aa It is expected these benefits would be mostly iimited to Plfs and RBC prqiarations. However, in order to assessthe cost-effectivenessof PRT without considering a potential FNHTR benefit, w set the residual risk of th.is event to zero which removes this 2466 TRANSFUSION. Vdwe 50, Novsb€r 2010 adverse event and associatedcosts from the model, The: whole blood PRT resu.lt increased to $1,364,000/QALY representing nearly a 7% higher cost-efectiveness ratJo. Appropriate values for the current residual risk for pathogens that are not universally screened for are dificult to knN with certaint]4The influence oftwo infectious threats, bacteria and T. guzL was assessed jointly. If the underlying residual risk of bacterial infection for all componenF is I in ?5,000and for T, cruzi is I in 250,000,the cost-effectivenessrado for whole blood PRT increasesto $1,876,000/QAIY (95% CI approximation, 812,000. 5,295,000),Teprsenting a 47% higher cost-eFectiveneEs ratio. 卜Ｎ Ｈ 古８ ． ８ 歯悪 ｇ 一食０． ８ たこ ｇ 一，８ ． ８ ●¨ ヽ一 Ｒ 〇一 〇〇０． ０●ヽ” ８ ２ 一３ ヽ コ 長 ﹂ ０ ，と の０，Ｐ Ｃ 彎〓＞ ヽε ，Ｏｃコｙ〓０ １ ＞Ｙ一 工０ ０８ ヽ 毬 ９Σ Ｏの Ｂ Ｏ ● ｃ，署 馬 ０ 百 督 置 Ｓ Ｅ に ０ ， ０ “ａ ご援 ｐ Ｏ φ 十 一 ０〓 芸 こ Ｃ Ｏ 〓 ｏ 〓 ３ ど ヽ ２ ・ ６ ， ， そ ０３ ８ ７ ● ｃ８ ０ＥＢ 資 ０８ ． ０， ヽ キ ヽ も にｂ ● 〓ＯＲ曼 当 Я０ ８ Ｓ ¨ ． ｃｅ ＯＥョ ４ ８ ， 受 ︶ ミ一 一 、 ｔ” ８■ ３ ８ あ ｂ ８ 異 螢 ︶ ■ヽも 籠ぜ●Ｏ Ｒも Ｒる． ヽ一 ． Ｒ舌０¨ ｔｐＯ ｏ Ｓ” ｐ〓︶ ＩＮ焉 一 ． ”¨ ＯＥｏ〓∞・ ０ ９Ｘ︶ ｏｎヽ一 霊Ｒ一 ． こ 卜ヽ ” 笙ご Ｓヽ Ｒ お む ” Ｅ Ｅ Ｄり ， こ ｐ ﹂ 一 ・ 一ヽ ． １ と や 娑 囁 薔 ， 卜 も ● Ｐ ｏＮ 主 ●買 ■ ８ 一 Ｒ る ． ＲＶ ミ ” § ■●も ｒ，Ｆ互Ｊ● ＲＯ． ０９” ・ ． 〓●●Ｅ薇協く Ｒ８． ＯＸ︶ ０こ¨ ●９“Ｅ一∽０ メモ と０﹂マ︶ Ｅ ，毀お ﹂ ｏ ８ ８５ 雲 き や 無５８ 一 Ｓ ●３ ｔ ｅ ョ０ Ｅ ２ ｏ Ｌ お 雲 ざ ＯＥ ９ 〓 ＾い ヽ ” ¨ ヽ Ｒ ご ● ５ ヽ６ Ｅ ２ 工 ¨ こ じ 己ＯＬ おＬｇ蜃 ヒ９ ‘ ヽ９ピ コち， ● 燎 工 ¨ ８ 理笹 一 ●● 里 ●■ ¨ ｇョ０ち番こ ヽ９Ｅ ョリ望ヽ ■Ｃ” 口やｏＣ●Ｏ Ｃ¨■ご●〓 Ｃ〇一 ＯＣ”● ”Ｓ，こ ョ０ ． 堡逗一 卜“ ● ●‘ ¨ ● ｕコ∞ “ ト ，マ ，３ 鳥 じ ０ ３ ●Ｓ ５ 一 ちＣ 一 ︱こ ６電弔 ゼ ヒ● 2464 InANSFUSION Volume50,November20l0 Canadain2007, and so no scteeningcostsare included for this agent. CMVmtibody add gamma irmdiation costsne .assumedto be incurred only for the units intended to be uansfused to patients with underlying immunocompromise. The estimatedcost ofPRT ($100on a per donation or component treated basis) covers the cost to implement t}re suategy including labor and overhead. In the case of bacteria.l cu.lturc, costs are not incurred for all components as screening is conducted only on PLTS.PLTScomprise l0-15% of a.ll components transfused in Canada.'?2 We used a cuffency converted, inJlation-adiusted cost estimate for bactedal culture from the Netherlandss to determine a cost of $25 for bacterial culture per PLI prepila$on. The potential risks of riboflavin-based PRT include c)'totoxicity, genobxiclty, and reduced efficacy ofcomponents. It is pgssibleproc€ssing mistakessuch as under- or over-exposure to. W .light may lead to these consequences, but available laboratory and aninal model studies conducted to date have found only minimal widence of these adverse events.z3It is expected rhat BBC and PLI efficacy cou.ld be reduced by the ueatment process,but the oneavailableclinicalstudyof PLTstreated with riboflavin.based PRT did not demonsuate increased trmsfusion in the PRT treated compared to untreated arms of t}le trial.za2s Nonetheless, we included a component use cost factor in the model to accoui foi potential additional transfusion of components due to the PRT ueatment process.We reflected increasedcomponent use by assuming a l07o increase i.nblood component screening and preparation costs t}lat would be necessary to achiwe the same therapeutic efficacy in the PRT arm of the model. In sensitivity uallsis we varied this additional cost factor between D and 20%. COST‐EFFECTIVENESS OF PRT CuSTER ET AL: deFendent on the pooled PLf pleparation method. The residual risk ofbacteria in plasma-rich PLI preparauons is higher than in bufry coat or apheresis preparationsi thus PRT treatment of PLfs prepared using this method yields greater benefit and a more favorable cost-effectiveness profile. As the percentageof slngle-donor apheresis collections increases, the costeffectivenessratio increasesin a nonlin€il mmne! and at I00% single-donor collections, the ratio exceeds $2,000,000/QALY TABLE 5. Costs and sllecls ot _currentinterventlons, wlth PRT and incfemental cost-effectlveneasot pFT by . lianstusjon reclplent rgs group tor PLTs-and-plasmapBT ; R 酬 時 c a t eり g ●: 警]『 齢期i騨ツ 4437 7838611 4465 4436 1945o178 轟 hittT辟 d PRT,C,0/° ALYl(8141″ :部 湖橘器:“ ::♀ :,00 6 E S Z [! ! E E E Z (! E g .“ 総:::,∞ 。 19651濯 1 9:,∞ Q mortalityprobabllityIn y€sr ot tianaluslon: O,1O to 0.30 componentspeclflc mortatityadjustment:Oto '1,5 donor exposurcr non.bactqrialagents per plateletprgp.;6 to t donor exporures bacterlatper platglsi prep.: 6 to I prcbabitltyof sepsiadeath,immunoqomp€t€nt: 0.5to 0.3 dost ot PRT pd d onatton: {.75to 1251.0.25 dlscountEte for sffects:0.01to 0.05 OoL w€lght for oonsequencesol sripsts:0,59to 0.79 OoL wolght In yoars tollowingtransfuston:0.99io 0,86 componentuse adlustrnentfactorfor PRT:1,0io 1.20 ptobabilityof T cruzf: 0.0000075 tq O.0oO0O25 % dsk reductlonadlustment mir€d compan€nltEnsf.: 0.75to 0.25 PRTadiustmentfscior for FNHTR:2,99to 1.01 annualmortalityalbr annafusion:- to +25Vo probabllityot deathIn acutET. cruzi stat€: 0,03to 0.001 dlsutilltywElghtfor FNHTR:0.02to 0.005 probabllltyot FNHTR:0,0002to 0.00067 mortalityadJustmont tor lmmunocompromised: 1.0to 1.8 0% 40% 8% ノ 一 ″ ',イ (lmillionsrOALY) showlng the range of values u6ed md resulto from one-way sensidvlry uallsts abts tr rh€ P[Is-and-plMs pulded ftom lN PlTs-.nd.plasma PRT model. Eeh horizontit to htgh or ldgh to low tn corspondonce bu relles the mge wlth the left ud PBT We rcpott the costs and consequences of PLTs-mdplasma PRT compared to current screens and interuentions used in Canada (Table 5). When evaluated on an all-transfu sions basis, the incremental cost-effectiveriess of PlTs-and-plasma PRT is $1,423,000/QALY (95%.CI apprcximauon, 834,000-2,818,000).The mean gain in quality-adjusted life expectancy is I I minutes per patienu even though the incremental cost is also lower, the cost-effectivenessof PLTs-and-plasmaPRT compaJed to cdnent screens and lntepentions is less cost.effective than for whole blood PRT.This result is expected because of the decreased overall risk reduction achieved using PITs-and-plcma PRT compiled to whole blood PRT.The pattems ofcost-effectivenessfor older md younger Eansfusion recipients ari: similar to those seen for whold blood PRT with estimated Lost.effectivenesscif $42S,0OOiQALY of adl@m vdus of the mGt lntlu€ntlal wrl. llsted m rhe rlght, Ruges ue bu. QoL e quality of lue, rlght €ndc of each horlzontal (9590Cl approKimation, 256,000.805,000)in trmsfusion recipients 39 yeds or.younger in age. PLTs-and-plasma PRT sensltivlty analysls In bne.way sensitMty analysis; the factors that are influential in the PlTs:and-plasma PRT model in order of decreasin! influence arc monality in the year of transfu. sion, mortality associatedwith t'?e ofblood comporents received, the number of denor exposuresper pooled PLT preparation, the probabiiity of death due. to sepsis, the cost ofPRT per donaticin,and the djscoun! rate for effects (Fig.2). We examined the sensitiviry analysisresults with respect to donor exposures in more detail b1i evaluating the influence of the percentage of single-donor PLT (apheresis) collections on the cost-effectivenessof PRT based utren the pooled PLT method is eirher bu6/ coat or Volume 50,November201o TRANSFuS10N 2407 s1yo _ 1@yo of PLT preparatlono fiom slngle-donor aphsGls collectlons on tha lncremental cost-efrecti@Gs ratlo (ICER) of PUI8-md-plssma (reens od lnterentlons. (+) PRT compiled to mt Bufrycoat randm-donor PLTs; (+) plasma.tleJr tildom-donor PLT!. ′′ Flg' 2. Tbmado dlsgrm Piobabillstlc sensitivity anslysls 60% Psrcenttge ot PLTs frdm single.donor apheresis colloctions Flg, 3. lrlluence ofthepercentage ´′ ・ ／／ ! S Z E F lncromeni6l CosUE foctlvenesr 7266393 3 1各 帥 Ⅲ 蘇 Ⅲ ︵ ンヨく０あ ︶α”０一 T● ●l crlst rOr.υ ″ent s● 7● ●nJ":07Ven"Ons(sCAD) e c l s u t h c u m nr l● E“ o∞ n s nハt e r v oO nn “ s(oALY) The cloud diagr6ms of the incremental costsand effects,gerreratedfrom prcbal bilistic sensitivity malysis of whole blood PRT and PlTs-and-plasma PRT prwide an indication of overall unsertainty, As expected, the simulauon resuJl plots show that both the incremental cost and the incrementat effec- . tiveness of whole blood PRT are lrigher than for PlTs-and-plasma pRT (Fig.4).@ In addition, .the possible valueg forN, incremental effectiveness of wholed blood ue more uncertain thm those for PlTs-and-plasma PRT as demonstmted by the greater hbrizontal dispersion of individual simulation resulB. DISCUSSION In this analysis, we assessedthe costeffecdveness of PXT for whole blood focused on the dLect cost of blood safety interventions and medical care. 0,m000 0.00oGt 0.00005 0.00m8 0,0m10 0.m013 0.00015 0.0001! 0.00@0 While such a technology is cunently . Incrcruntd Efioc{vgn.ss (eALy!) unavailable, clinical studies of candidate technologies ani under way, We Flg. 4. tnqemental coat ud effectlwness scatterplot6,from 2000 probsbiltstlc 6tmuestirnated the cost-efiectiveness of lations for whole blood Piff compded to cuent scEetrs ud PlTr.ud.placmq PRT adding whole blood PRT In Canada to to culmt ercss. Soltd lhes repsent comped dre mes lnqemqtal @Etcurent screens and intetrentions to be €F@tlveness ntlo ud dashed llno represent the 2.5 od 97.570 wlu6 of the costRecognizing.that $1,2?6,000/QALY. RBC efrectlwnG retlos hom the dlctrlbutlons ofthe slmulodons u'lth polnr forwhold 'risk would not be mitigated by cur. blood PRT shm ln gray ud potnts for PlTs-ud-plsma PXT ln blqck; llnq re ln rently available PRT we modjfied the reverse graysele so thFi tiey can be vlsuallzed on top of esch correspondlng cloud model and used it to estimate the increof pohrs, mental cost-effectiveness of adding PlTs-and-plasma PBT generating a result of $1,4?3,000/QALYcompared to current screens Plasma-rich prepilation6 (Fig. 3). When no PLIS are prepared using single-donor colleciion methods, the increand interuentions. The cost-efectiveness of a PLTs-andmdnlal cost.effecti-rrenessof PlTs-and-plasma PRT is plasma PRT was most dependent oq the PLf collection 2468 TFANSFUSIONVdume50, Novomber2010 COST-EFFECTIVENESS OF PFI and preparation methods used byblood centers.The most important factors ddving better cost-effectivenessresults are the lisk of bactedal contamination and other infections r*ulting ftom higher donor exposwes in pooled PLls. Since Canadian blood centers collect and prepare Plirs via single-donor apheresis or bury coat prepilaton methods PRT technglogy will be less cost-effective in Canada than in counl$es which primarily supply plasmarich PL'IS. The analysesreported here with respect to the costeffecdvenessof PLTs-and-plasmaPRThave foosed on the mix of PLT preparation methods used by Canadian Blood Sewices. HemaQuebec, the other blood operator ln Canada,which servesthe Provirrce of Quebec, uses a different combinatlon of preparation methods. Approximately 80% of PLTscollected by HemaQuebec are from single-donor apheresls collections with the remainder of PLTSproduced in 2007 being plasma-rich PUfs averaging five donor exposures.Tbis combination of PLT preparation methods leads to a result of$1,389,000/QALY(95%CI appmximation, 713,000-2,944,000)for.Plits-and-plasma PRI The same percentagesofsingle-donor apheresiscollections and bufu coat-derived instead of plasma-rich PLfs as now used by HemaQuebec would lead to a result of $1,775,000/QA!Y (95% CI approximation, 1,021,0003,364,000)for PLts-and-plmma PRT. On the one hand, ifPRT were to be adopted it coutd be more cost-efective than reported here.The residua.lrisk of Fmsfusion-uansmitted viruses of greatest concern is alreadyvery low particularlyin Canada, due to the ef0cacy of current screen6and intewentions, and in this analysis we did not a$sume that any of these icreens or interyentions would be discontinued or modified. However, it is likely that blood collection agencies would seek changes. Interyentions tlat potentially could be eliminated include bacteria.lculture for PLfsand gamma lrradiation. Interventions that could be modified include universal tesung for WIW md HTLV For example with an available whole blood PRT'discontinuattoir of testing forWNV or elimination of outbreak seasonindlvidua.l donation nucleic acid testing (NAT)might bepossiLledue to the more than 5 logs kill achievedusing riboflavin-based PRT,2'and discontinuation of bacterial culture of PLTSalso seems feasible for eitber a whole blood or a Plls-and-plasma PRT.z8 Each of these changeswouJd favorably alter the incremental cost-. effectivenegsof PRT Avoidance of T cruzi screening also seens likely given the obserued ability of riboflavin-based PRTto inactivate this and other pdasites.'?s On the other hand, ifPRT were to be adopted it cou.ld be less cost-effectivethm reponed here. The potentia.lfor ilireased component uEe,adverse events forblood recipients, increased treatment costs, md increased total costs to the heajth care system could result from the use of riboflavin-based PRT. For exmple, the formation of neoantigens is possibl€,Basedon other PRTmethods that do not use riboflavin as the photoactive compound, this could be an issueforRBC units prepared from PRT-treated whole btood.3o,Another possible concern is for PLTS ueated with PRT where clinical studies including the MIMCLE trial have shoM that the corrected count increment (CCD is lower for PBT-treated compared to untreated PLTS.25 Lower CCIScould lead to increased risk ofbleeding. The cufent analysis does not consider other infections such ashuman paryovirus Bl9, rabesia, ortheund€fined value ofPRT in preventing transfirsion trmsmission of un-knom or reemerging pathogens, The safety and health edonomic benefit ofPRT in the face of m emerging agent could be considerable. Most infectious agents (except prions) would likely be at least partially susceptible to PRT.Weelected not to include such an agent in this analysisbecauseit is reladvely easyto constluct the set of 6sumltions regarding th€ pathogen so that resujts create a very attractive economic profi.lefor PRT.Adopting PRT could be thought of as insurance against the risk of a future large epidemic of an un-known virus, bacteria, or parasite uansmitted to transfusion recipients, th the tace of a prevalent emerging pathogen it.is highly likely that whole blood PRTwouldbecomemuch more cost-efective than PLls-and-plasmaPRT alone becauseoi rhe reduction of the threat in all blood components. The residual risk of many infectious or noninfectious threats is imporlant for tle cost-effectivenessof PRT,but limited data are avbilable on objectively measured risks of many potendal adverse events associatedwith uansfusion. For example, the mo$idity and monality of bacteria-contminatedRBCsarc notwell defined.Quebec hemovigilancedatarepon that bactedal contamination of RBCs occurs with a prevalence as high as I in 36,000,,? whereas others have estimated the risk to be approximately I in 250.000or lower-rr The frequency wirh wNch such units result in detectable clinical morbid.ity or mortaliry afects the calculation of cost-effectiveness.In our analysiEwe assumed that the baseline residual risk ol bacterial contamination was t in 50,000and that 40% of nonimmunoiompromised patients who received nonPRT-teated components containing bacteria would develop fatal infectionsiActive capture of data via hemovigilance may provide reliable estimates,but the availabi!. ity ofmore precisedata would improve the accuacy ofthe analysis of infectious Jisks acloss all blood component fypes.The importance ofcu[ent residual dsks ofin-fection. was also exhibited in oiher sensitivity malyses. When we reduced the dsk of bbcteria md I cruzi at the sme time. the overall cosi-effectiveness ratio of whole blood PRT incrdased by 47%. Our analysisof the cost-effectivenessof whole blood PRT h6 impo(ant li.mi(ations. To model the question of the cost.effectivenessof PRTwe had to make severalsimplifying assumptions. ln one simplification, we msumed Volume50, November2010 TFANSFUSION2469 CuSTER ET AL. that $ansfusion episodesile one-dme events with exposure to one whole blood unit or its equiva.lentcomponents. This does not reflect clinical practice because transfused patients may recdive mu.ltiple transfusions on difierent occasions, and even in the same tarisfusion episode patients could receive mywhere ftom I unit of any component type to dozens of units. The model does not account for tnnsfusion of different nmbers of components or multiple uansfusion episodes.The swival of recipients of a large number of units in a singl e tran sfusion episodeis signific'dn0ylowerthan recipients who receivea smaller numberofunits.rs,rsIfwe were able to account for thjs in our model; the cost-effectivenessratio of PBT would be larger than reponed here. Akey frcior relatedto blood recipients thatwe camot addressin the ma.lyslsis the possibility that curent posttansfusion swival acrcss all component types, but particulnly for PLI recipients,maybe lower than the supiva.l probabilities we used.'Changesin practice pattems such as increaseduse of P[fs in patients with poor prognosis and reduced life epectancy wordd lead to larger costetrectivenessratios. While clinicims may recognize that current survival lates.are lower for palients who receive specific blood components, only published longer-term suMval data are appropriate to include in malyses of the cost-effectjvenessof blood safety interuentjons. By necessity long.term posttransfusion swival data relies on tansfusions that may have occured as long as 20 years ago. Policy analysesthat rely on posrtransfusion suryival data carinot circumvent th.islimitalron, Anothel potential limitation is the inclusion of some noninfectious advene events such as postoperative infectjon that might occur as a resu]t of TRIM. The debate i,s ongoing as to whether this is a real phenomenon leading to jdentifiable health consequences.s233Nonetleless, assumingthai the phenomenon is iea.lthe idea thatTRIM is influenced byWBCs ls less conuoversial. PRTwill inactivatel trBCsthat afeirot removed by leukoreduction, pre. venting antigen presentation that could uigger recipient inmune system respoirses.In this analysis, we assumed that PRTmuld achievea 50%reducrionin the residuai risk ofoccurrenceofTRIM. Moreoverre modeledpostoperative infection atributable to TRIM by assuming that the dskreduction couldbeas lowas l% or * high as a twofold hcrea,se.In sensitiviiy analyses,no aspect of TFIM.was influential includingthe assumedrisk reduction achieved using PRT. Arother posslble limitation is that there is currcntly only emerging clinical data to support a redriced rate of FNHTR after the adoption of PRT.However, the mechanism for at least some FNHTRs is thought to include residual WlCs and PRT could reduce the freouencv of FNHTR as has been observed in clinical studies. These benefits would be.expected in componen$ that carry higher risks of FNHTRS:PLTSand RBCS.In the model, 2470 TBANSFUSIONVdume50, Novembsr2010 FNHTRS arc relatively high-probability and lM-cost eventsthat desomewhat intluentlal. IfFNHTR risk reduction is excluded froin the model, for whole blood PRT the cost-effectiveness mtio increases by approximately ZVa (meaning PRT is less cost-efrective when FNHTRs are excluded). However, the 7% efrect oi the ratjo shows that FNHTRS are not overly inJluential with respect to estimated cost-effectivenss. The PLls-md-plasma PRT model also hm imponant additional limitations. Chief anong.them is i}lat, except for donor exposuresassociatedwith PLTs,the model does not account for difrerential risk trsociated with di$eren( component types. For example, the model csigns the risk for plasma equal to that of PLIs for rhe uansmission of enveloped viruses such as CMV or H'[LV and for FNHTRs risk reduction. Ifother infectioss or noninfectiou$ threats di.ferentially partition to specifc labile blood compo. nents, th€n the model does not fully reflect these differendal risks. However, we did account for one of rhe most important influences on the residual risk of bacteria.l contamination-the method of PtI prepuatlon3'-and showed th3t the cost-effectiveness of PLTs-md-plasma PRT vilies depending on PLI collection and preparation methods. Another importanr considerarion is how we modeled the residual risk of each adverse event in the PLTs-andplasma PRT anal)sis. The infectiousness of a blood com- O\ ponent is dependent on multiple factors; these include N the stageofdonor's inJection atthetime ofdonation [viral H load and antibodylevels), therecipient's immune system, and the interaction between the two,r among other factors.3s36 An additional factor for component.specific use of PRT i$ also present and is related to the approach we used for modifying the residual risk of uansfusion complications based on the combination of components transfused. For persons who receive transfusions that include both pathogen reduced and nonreduced components (RBG), the residua.l risk of an adverse event is adjusted to reflect a blend of the lower risk in the pathogen-reduced component coupled wirh the residual risk of the norueduced component. Emnomic evaluations of simild PRT processeshave previously been reported. For example,studies ofthe costeffectiveneqsof amotosa.len-basedPRT for PLTsfomsed on patients with specific conditions requidng transfusion, l A study conducted in the US setting reported results for four different latient groups (pediatlic acute lymphocytic leukemia, hip artlroplasty, coronary artery b)?ass grafts, and adult non-Hodgkin's lymphoma). and with and without bacterial culture. Depending on the patient population, baseline results ranged from $4,8 to $23.0 million/ QALYwith bacterial culture snd $1.4 to $4.5 milion/QALY without bacterial cu.lture for apheresis PIJIs.3For pooled. PLTS;the cost-eflectivenesswas $1.0 to $6.0 miuion/QALY under assumptions oflow faiality atdbutable to baclerial COST・EFFECi:VENESS OF PRT COST・EFFECTIVENESS OF PRT less uncertainty, AII remaining model variables were vried within specifica.llydefined ranges based on published literature or standardized methods. Probabillstic sensitivity analysis (Monte Cdlo simulation) allows for an overall assessmentofthe uncertainty given the range of poseible values or probability distdbu. tion of eachvatiableused in the model. We ran 2000 computer simulations of each analysis and ob{ained an afrprcximation of the 95% Confidence Interval (CI) for the cost-effectiveness ratio; reprcsented by the 2.5 and the 97.5 percentiles of the distdbution of results from each simulation. PLTs-and-plasma PRT We modified the whole blood model to estimate the cost effectiveness of PRT for the technology that is curently approved for use in some Europedt jurisdictions, PLTsmd-plasma PRT.To do so we added an additional secrion to t}le model focused on PLI preparation metiods. As in the whole blood model, transfusions containing PLTsare separated from transfusions not containing PLTs; this design also allowed us to include the PLI prepilation method (single donor or pooled PLIs). We assumed single donor PLIs represent 25?oof the total prepaiations and bufly coat PLT preparations represent 75% of the total prepilations (percentagesthat approximate the prepilations issued by CanadianBlood Services).Thebaseline risk for PLTSin this vercion ofthe model applies to slngle donor preparations and.a donor exposuresfactor is included to increasethe baseline riskfor each adverse event aciordirg to.the numbei ofdonor exposues for recipients ofpooled. PIXs, In the PlTs-and-plasma analysis,except for bacterial contarnination, we assumedthat therisk ofplasma was the same asthat of?[fs and that PRTreduced those dsks to the same degree in both products. Fj€ept for transfusion episodes that include both PLTsand plasma, which are included in the PLIs arm of the model, trmsfusions that include plasma are considered in another separate um of the model. PLTs and plasma account for approximately 25% of the components transfused in Canada'! so the effective cost of PRT on m all uansfusions basis would be approximately 25% of the bost ofwhole blood PRT if fixed costs are not considered, However, the risk reduction achieved for this cost is not 25% of the overall risk because different combinations of blood components are transfused to patiehts. To estimate the averageexpected eFectivenessof PLTs-andplasma PRTfrom the perspective ofall components transfused,,we adiusted the risk reduction achieved using whole blood PRT.We assumedthat patients receiving RBC only traasfusions would continue to have the same residual rlsk with no benefit from PRT For patients receivlng iransfusions that de exclusively PLTs and/or plasma, representing nearly 15% ofthe transfused popu- lation, we assumedthe riskrcductionwould be equivalent to the overaJlrisk reduction achieved for whole blood PRT (Table l). For the. remaining lQ% oi the uansfused padents receiving combinauons of RBC,s,PLTs,and/or plasma tFnsfused, we assunied half of the current dsk would be mitigated, meanlng that the residual lisks.for recipients ofRBCSwith PLTSand/or plasma is the average ofthe curent residual liskand the expectedlower residual risk obtained by the use of PRT for PLTsand plasma. RESULTS Whol€bloodPRT We repon the estimated average quality-adjusred life expectancyfor the trmsfused population overall and for sprcific recipient age groups, th€ average healthcarerelated costsincured per donation with current intenentions, md incremental cost-effectivenessof rqhole blood PRT ccimpared to current interyentions used in Cmada (Table4)..For all recipienk, on avetage individuals are expected to gain approximately 47 quality-adjusted life minutes. ln a cohort of 100,000tlansfusion recipients this would represent a gain of approximately I qualityadjusted life yeals. The incrementa.l cost-effectivenessof whole blood PRT compari:d to current screensmd interventions is $1,276,000/quality-adiustedllfe-yeu (QALY 95% confidence interval [Ct] approximation 600,000Fortrmsfused padenr over40 yeils of age,the 3,313,000). incremental cost per QALYsaved is higher, but similar to the ovemll result given that the averageage of tmsfusion is approximately 65 years in Cmada. However,for recipients 39 yeals of age or younger the incremental costeffectiveness is $a26,000/QALy (95% CI approximation 197,000-1,173,000). Whole blood PFT sensttivity inalysis One-way sensitivity analyses are shown as a tornado diagram for the overall recipient population (Fig. 1). In order ofdecreasing influence, the model is mdst sensitive to the risk ofbacterial containination, arnual mortalltyin. the year oftransfusion, dre cost.of PRT per donation, the probability of death due to sepsis, the discount rate for effects, did health, state quality.adiustment preference weights for patients requiring transfusion in the years fol. lowing transfusion. Bacterial contaminadon risk js the most influenual vuiable and a low dsk for bacteria (1:100,000) leads to a cost-effectiveness of nearly , The lmpact of posttransfusionmoilality $2,200,000/QALY. in the year oftransfusion is shown in the second horizontal bd of the figure. Low amual monalitywould lead to il incremental cost-effectiveness of whole blood PRT of $850,000/QALYwhereashigh amual mortalitywould lead to an incremental cost-effectivenessof whole blood PRT of$l,550,000iQALY. Volume50, Nov€mber2010 YRANSFUSION2465 contamination and improved to $460,000to $i.8 miluon/ QAIy assuDing bigher fatalily due to bacterial contamination, Similar analyses for specific patient populations were conducted for Belgium, the Netherlands, and Iapan.'6 Arother study from the Netherlands found the cost-;ffectivenessofPRT for PUls to be 92,8million/QAIY (approx. $3.6 millionlQAlY) when added to bacterial culture and €382,000/QALY(-$497,000/QALY) without bacterial cultw in rmdom-donor PLfs for the average recipient.eThe maiority of these results suggest a costeffectivenessof PBT.that'is less efncient than we report here. These pleviorxi aiialyses did not include the broad range of infectious ild specinc noninJectious tfueats that were included in our analysis. In addition, many other analy$isassumptioDsrlveredifferenL maklng direct comparison of our results to these studies dif$crdt. Nonetheless, one common thread is apparent: bacterial contamination is the most impdrtant knom adverse event that PRT addresses. Our xesults also indicate drat the age of the patient popu.lation is an important determinmt of the costeffectivenessof PRT, In the previously published costeffectiv€nessstudies ofPRT for PLTS,the best incremental cost-effectivenessratio was a.lwaysevident for the pediat. . ric population.3{ We conducted our analysesfocused on different age groups to show that there ae subgroups of uansfused patients where PRT has a relatively atuactive econoiric proflle. Thgse analysesare intended to indicate that for rhe expected benefrts to accnre to subgroups of patients, it may be necessaryto adopt PRT for all blood collections.Only ifseparate b[ood supply inventories were kept codd recipient:specific use ofPRT be an qption. The copplexity ofmaintaining separateinventories on such a large scale has not been carcfully studied, but in many setdngsis likely not feasible. Model var.iablesrelated to the age and heajth statusof the uansfused population had important inJlu€nce on cost-effectivenessresults, ln addition. the discount rate for effdctswas influential. Discount ntes reflect time preferencefor health and money, with higherpreference given 1o havlng health and money today as opposed to in the future. These model vuiables are not directlv related to PRT and are often influential in anallses oi any blood safety lntewention. Moreovet the influence of life expectancy, quality oflife, and discount rates is applicable to all cost-effectivenessanalysesregardlessof medical practice area. Both appropriately accounting for quility-adjusted life expectancyacrossbroad population grcups and determining what discount rates lo use are uroesolved methodologic controversies in health economics. While the influence of these variables in the analysis is evident, whether these varlabl€s have meaning with respect to decision maling about PRT adopdon is unclear Relative to the cost.eflectiveness of interventions aheadliin use in Canadaand many other developedcoun- tdes, $uch as minjpool HIV and HCV NAT, which exceed the estimated $1.5 miUion/QALY in the United States,3'.3o preadbption cost-effectivenessofwhole blood PRT and of PlTs-and:plasma PRT is consistent with established thresholds for ra.lue in blood safery In developed counuies that have very low risk ofuansfusion transmission of infectious diseases,wen if some curent screensor interventions re discontinued oi.modified, it is unlikely that any PRT tvill approach an incremental cost-effectiveness ratjo:threshold of $100,000/QAIY ;qJthoughexpensive on a cost-per-QALY basis in comparison to interuentions adopted in other sectorsofhealth care,given blood Safety. expeitations that lean toward f'zero rjsk" for infectious thats; commonly accepted thresholds that are regarded as cost-effectivein clinicaj practice do not seem relevant. There continue tobe multiple difrelenthsards associated with transfusion including thosg considered in thls analysis and other ones not amenable to the use ofPBT such as trmsfusion-related aote lung injury ahd transfusion of the wrongblood type. TNs cost-efrectivenessmalysis provides additional information that was.not previously avai! able and may help to support decisions regarding thls technologywithin the context of competing interyentions and other threats to the safety oftransfusion. coNFLtcToF TNTEREST o This resealchwassupportedby an srestricted grmt ftom cd- fv.) idianBcT (Lakeland,CO)..CaidianBcl proridJd no editorlal H controlovei the resealchor the manuscript. REFERENCES l. Klein HC, Anderson D, pemardi MJ, Cable R, Carey W Hoch IS, Robitajlle N, SiviloItj M!, Sm€iI F. Pafiogen inactivation: makiilg decislons about new technologie$ Report of a consensus conference. Tlusfusion 2007;47: 2338-47. 2. Kiein HC, Anderson D, Bemardl Mt, Cable R, Carey W Hoch ,S, Robitaiue N, Sivtlottt ML, Smaill F. Pathogen inactivationi making decisioN about new technologleF preliminuy repon of E consensus conference. Vox Sang ZOOTig3ilTg-82. MF, Gao L welssfeld JL, Postma MJ, ' 3, Bell cE, Bottemu Pashos CL, Tdulzi D, Sraginnus U. Cost-efectiveness of tBnsfusion of platelet components preparcd wlth pathogen lnactiEtion tEahdBnt in the United Stares. Ciin Ther 2OO3;25:2464-86. 4. Moeremans K, Wdie H, Annemans L. Assessment of the economic @lue of the INTERCEPT blood system in BelglM. Tlanstus Med 2006;16:17-30. 5. Postma Mt, vatr Hulst M, DeWolf fI, Botteman M, Staginnus U. Cosl.etrecilvenees of pathogcn inactivation for platelet tlansfusions in the Netherlands. Transfus Med 2005;15:379'8?. . Volume 50, November 2010 TRANSFUSION 2471 CuSTER ET AL. 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'ltKPlqld4 hdm Enrdd.4, o'!$ cd26i!h tu3sr..{uru.ldnrP,Ir here!8&trdirc 2r tuMtdod.dEt.lle$drtulp.^'ed, !iMd,o.onda@. rd2ooerd$t.Mdr. dDfturlhr9//tlM..ll,.dbrdvdrrdrG bd.btuddddudreFtu uooddoLdo*lhllrls!!@ds,'lr rddvddrletlrbdddt,]rMlhl'4n $. ibe.lqgJ. trc Db.renr*r, Ddrs! q u, srlrEM4!6McturdlE,GoldMf,rd'Imr.du6nftl|lhloo.alrtutuxrqo:6@.?5 c.e!D.if [email protected] ' d.d@ tu'qdd4dt{trilllldrury$hnd o a &6tm,ftr!s,L<I!ir6z.sb.dw'xitt dd@sl!6hD;dddetu,tod4Id E ltds.rsoEesd'dFd,i,tud. ;;;-* s6roi t, ogIr tP,hnmdb P crnud o Ddld ,e wa;ovc,sor c*m.x.o,mn -aru. r.sch,",@",!bo.^'.fu".sdre",s ;-;;4;;-td.;;;-;is4 tu*lbn r,tusb|dM.Mftr-toht tuc lotldaGqs.q ndm;&dd.riepedond' drse i. tidD D,l k.*c hod d tt4ch'uec.utuM FEtul,tuco.b !, tulEell,lBu,rob&inF,u tupdP. bdrrorolH.d,stl..MhdDrdd66n ;E .tu.ptueided. r.Fbcs,tuB.b*6.lffinaolp.djd hE.k$.4lc&2i@$rn ddFbn. 6tueod/btllnduirwrjL'rr.d.rim Dfu|fru6ddd'adddxm.Ml'i''Ml*'bfuh'a,wD'dsD'bd|dR!cdIorlb.dncI. r.. bF+r@r!,abl9ar,ihg..nr,Eq!u, drrdrRP.rnedwir.rrheddof d.isdtfu, Et@ c NFo, b{ly s, lrodr t liduud x, rttd a ud b&dr. h pr.rd.!@@nb,c dngnh.6$ Dd slirbs.eiiyn.fir6bodd*nerfrstucs lrrhrnrdfdoolilMr,d 2.ei{rM.4 a, <;d.hs,6r!'ND,a.l@!,Ld3''ardjtury @F,'Iofpdoen'tdldhldslryrtl$l .fi'!-,ir&ba.s.dh.Lqnidrsss ddlM..pr.r|aDodu.atu .ndcdt|dd *ur..a- tubhdklM.tu rilrrr*i&ironll& '[email protected] b{'lM.dm*P''e u. u'l"ry, c,r* !dh!wu, ui!--r odt tuorbrod64ffirn bh!rtEtd4bhma , "-clrydldotquar","a'bqr/rybtr!, m a r,d, rdrd{6-lt*dF.rdr l4 hd;scl|dB.bngrm|llMrbddd ,uur-. m,n lo rq,irrzr,r. re. vf,lb n'. hr[' rw, vr4.s N, cn'r{ @. bns M.lltfufuud'qdu$'.|'oDuodbld 16. ndrhd!Notdl.{6!d'd &u&.rqrr@. 4, olfus,r5ql"hDw . rlr Pc cterlndd.e artui{iGlldd turxrlhDs,bf,. d..dtr&d ddd hrirdhdotu 2472 TRANSFuS10N Volum● 50,November 2010 -'*". d r. f. 4 .i qd! |@!y.i07.iL{nq6 oBd4rF,fnw.xc,YrQr.c.rdNM,rMrl\, lrtDilrtrdc, cl,l|ffiJr,wlmBllD, tuM, ru:!.G.D.dr5&h.!dd!cnrdbi'd.tu;Nood ntu.udra ?,rrturb2@rilsr. hc,r&lryqe,&nLod&rcshMsL ft.@d1lu&ddsrEbr6d,pdy,.E Dri!0o.2rit6 aupaoRlltitc tNFoFraallo ^ddtrldd $pponhs Ltodrron onljr.yndmdihr,rdde lEbr.{ apr.tdirth. ortor,,n r s b.y bc t'ud , rn tlE !!dn{iE ordhoso rry i md!C' * dcsdonaodd Pl.4. nde: wlLyrladwlt s Nr Eimrbt torfi. oD@rortu& dlrrrryotuy.uppodrlgmrdn..uF qu.G rot}'q $u h!dn! 9kd ry n'. $l}sr,^ny l*dlllhoddbsdkddbfism.pordr4Nlndi rt"ar,a- urroleq 4, crdo u,6.Lu,, &!dsr, i.ndy D,eodnd & h'n . !.6*dndddltnltlt@d."lhpLi{rad dq tu d uEsL'LghL ad. s.ohb il|e. rFbdsd rdttt3lz $. sfrs,s.crtnLnJ,lli&qu.bd!'tuF E, eriilrx,u.:nD. bEL8kbdrrFd.fl. sM6s.sebi4dcMaqE(&6Dax|rddHl tuffid rlic4r@s. n!!ma@r@tcs edMDsd,LdlN,su{ntlP.I'ftcdvqothss l : . !.oAEh..d;sF!5Lz \r&lro tyg, adFco, t{i.$*iscD,E drux Fr6tntu@u4&dc@nedMd .i.p-*, * .*.a*,"a t"u,s "s,h." tsd.6rhe&ddekh!@mo$'s, -b.trN.rr"ed"h;"n"h.nt're&"* $. tun}!3c,!LFh!E4buitu.FhEdb* tu fiFn r d uptu. ldd k 2rdirrz !. rtfurc.raLeditla9oHftbed d. r!sdII-dm;(en4&) Volum●50,November2011 TRANSFuS:ON 2473 わが国における感染性因子低減化技術により生 じる使益 について (要約) 東京医科歯科大学大学院 ‐ 医歯学総合研究料 環 境社会医歯学系専攻 医療政策学講座 政 策料学分野 河原 和 夫 ‐ 方法 ￨ ` 輸血用血液製剤 に感染性因字低減化工程を加 えた時にいかなる費用便益を生 じるがにつ 術が確立 し、い 血 血 製剤ヤ 剤を含●すが て ￨ P,小 f製 ?摯 「 準 1技 FI愚 発警懲SIPイ ,経 済計算は、疾病や障害を有する者の生存期間を無価値的に提えた り結果が感覚 として わか りにくい QAIⅣ(QualityAdJusted LIfe Yё ar)で はな く、 具体的な金額によ り便益を算定 した. 保管検体で陽性が確認 された過去約 10年間の感染性因子の件数か ら1年 当たりの予想 さ れる感染事例を算定し、感染が成立 した場合の予後の推移等をもとに 「 直接医療費」 「 休業 損失」および 「 早世による遺失利益」を求めることにより便蓋を算定した。HBV、 HCV、 HIV、 細菌感染、と トパルボ ウイルスB19、HEVが 対象感染性因子である。 考察 ￨ : わが国では HBV感 染者が多いが、これは 「 直接医療費」 と 「 体業損失」の大半が HB▼ を原因としていることにも表れている。成人のHBV感 染の場合、慢性化 しにくいことから 1年 目の医療費等の出費が増大す るが、 以後ほとんど影響を及ぼさない。HCVに ついては、 慢性化する割合が高い ものの、IIBVに比 べ ると絶対数が少 ないことiし ょり、同様に経済的 影響は少ないものとなった。HIVに っいても同様である。他の感染性因子による感染が考 えられる事例にっいても数が少なく慢性化 しないものが多いことから便益は小額になつた ものと考えられ る。 まとめ 本稿では新興 。再興感染症 の流行の問題を考慮 していない。 しヽ かなる感染症まで対象 を 広げて経済計算を行 うが きか、そ して血液の検査や製造工程に どの程度の経済資源 を投入 す人きかについても議論が必要であろ う。 ＮＯＨ 結果 平均的動労者 (平均年齢 411歳 、年収 2945千 円)を モデル とすると感染性因子低減化 「 技術の導入 により肖1減できる年間の 「 直接医療費」は 24,298,786 Fl、 体業損失」,ま420,150 早世による遺失利益」は 1,088,669円 とな り、合計 25,8521698円 が 円となつたょカロえて 「 便益となる。 ￨ わが国における感染性因子低減化技術により生 じる便益について はじめとする新技術の導入は一般に高コス トとなるものである: そこで、輸血用血液製斉Jに感染性因子低減化工程を加 えた時にいかなる便益を生 じるか を調べた。但 し、感染性因子低減化技術が確立 してぃ る血小板製剤以外 の製剤も含むすべ ての輸血用血液製剤による感染を想定 した。 東京医科歯科大学大学院 医歯学総合研究科 環 境社会医歯学系専攻 医療政策学講座 政 策科学分野 : 、 どで身体が不 自由になつ■場合の生存期間を健常人が 1年 生きる価値があぅのを 03QA∬ に補正するなど障害の重み付けに主観が入ることや、疾病や障害を有する者 の生存期間を 無価値的に捉える問題があるもカロえて結果が感覚としてわか りにくいことか ら、本稿では 河原 和 夫 緒言 : なお、弩済計算を行 つている多くの論文では、生活の質 (QOL)で 重みづけを行い生存 fe“ar)を求ゅでい る。レ ust,dL■ 期FF5に ″￨え`牛 活の質の評価 もできるQttLY(QualityAф かし、QALYぼ 健康な人が 1年生きた場合の生存期間を lQALYと するのに対し、脳卒中な ' ￨ , 多くの方が直観的にイメ‐ジしやすぃょぅに具体的な金額により便益を算定する方法を採 高齢化 に￨よリョ騰すo医 辱費をいかにfrp制 するo)が、政●の主たる政策的謀題であるが、 医療技術 あ進歩 も医療費を高 しさせる要因の 1っである。 ￨ ￨ 用した。 現代の医療技術は、超音波、CT、IIRI、PETな どあ診断治療技術と人工呼吸器、人ェ臓 器(経 静脈栄養、ICUな どの延命的技術が主体となつている:対 象疾患も長期 ・慢性の経 過を示す生活習慣病である。治療期間が長い うえ:基 盤は光学技術や電子工学などの最先 方法 「 i 査や血液製剤の製造技術も同様に高度かつ高価な技術基盤 に基づくものである。N_ATや ウ 医療費出費、外来や入院にともなう休業損失、早期死亡による遺失利益を減少させるとい イルス等 め感染性因子低減化技術 もこうした技術に属する。 しかも、旧来の検査 ,製造技 ぅ社会経済効果をもたらすものと考えられる。 術 を併存 しなが ら最新技術を付力日しているのである。 血■分画製剤の不活化は技術 としてシステムとし`確 ユ してい る,論 ネ年、輸血用ユ液 製剤への感染性因子低減化技術の導入である。 検査技術 としての NATは 、血液中のウイルスを高精度で検出する技術であり、血液製斉J の信頼性の向上に大きく寄与 している。 しか し、費用便益面から考えると問題を有 してい る。NATと い う大規模技術の導入に当たっては医学面のみではなく経済的観点からの検討 ならびに導入後 の多角的評価が必要であらた。 しか し、それは十分にはなされてこなから た。感染性 甲子低減化技術も費用便益的観点な ら,分 析 ・評仰が 分とは言 。 ￨う 4な !ヽ す した大規模技術は社会経済的インパ ク トが大 きいにもかかわらず、医学的観点からの論議 のみが先行 し、そのほかの各分野の専門家、国民、行政、関係者を変えた議論の展開や合 意の形成 が欠落 しているのである。 本稿は、感染性因子低減化技術などの最新技術を導入す ることが、医療ゃ社会にどのよ うなインパ ク トをもたらし、導入 した技術をシステム として維持 していくために検討を要 する課題 の二部を整理 したものである。 ￨ 輸血用血液製斉1の安全性確保のた めに潤診の強化や NATが 行われている。また、血漿分 画製剤には不活化が製造工程で加 えられ、安全性を飛躍的に向上させている。現在、 これ に加えて輸血用血液製斉Jに対 しても不活化を行 うべ く議論が進んでいる。し か し、NATを 自未赤十宇社 には輸血後感染症 情報が医療機 関等力ヽ ら奇せ られ、保管検体 をもとに原菌 ウイルスか否か同定す ることになる。 これ ら報告 の うち、検体陽性 が確認 された件数 をも i鳳 こ 替 lご :お こ ど 桑 勇 1訴 ど 軍 [,1婚 hi鶴昼 昴 葉 靴I亀 ど 埋 重 iで :低 :る を導入し■場合)被 宣を防ぐことができ 、のとして社会的な観点から 「 直接医療費」「 体 .「 による遺失利益 業損失Jお よび 早世 」の計算を行った。具体的には、①感染により各段 "、 階に病態が進行 した際の'直接医療費 ②外来や入院に費やす時間に起因する1休業損失∵ 、 "を そして③期待寿命を待たず して死亡し￨“ 早世に事る遺失利益 社会的ョ挙 卜として算 定した。 . ´ HBVに っいては急性肝炎のステージで病態が終息するとし、 HCVに ついては慢性肝炎、 へ モ デルをもとに算出し た。 肝硬変、肝細胞がん の移行確率をMarkOv連 鎖 Vに らいて こと から 10年間においては死 軍 .(算定する今後 は予後が近年著しく向上 した 亡がなく、定常的な状態にあるものとした。なお、これ らウイルスの陽性血液を輸血され た場合、必ず感染が成立するものとした。 また、2008年 8月 より新 NATシ ステム (抽出 ・検出機器 cobas s401 試 薬TaqScreen ルF HBv)HCVヽ HIVヤF関する構 が行われていぅ:そ MPX)IFI,707ニ 草 ￨´ 1の NバTの 検出感度と現在のそれとの差を無視するが、2000年 ∼2010年 7月 までの約 10年 ｍｍ 出 端の技術で、 しかも開発途上にあるため短期のサイ クルで更新されていくものである。検 ' 1. NATを 行つているHBV、 HCVお よび Hrvに ついて 輸血用血液製斉Jの製造の際に感染性因子低減化工程を導入することはヽNATの 検出感度 以下めHBVt iCVお よび HIvの 混入による患者への感染を防ぎ得たことによる不必要な ０ ０ ０ ＾ ら１ ﹁ ０ ０ 為． ＾ 鳥０ 26oo年 ∼2010年 71月までの報告数 ０ ０ λ ん０ ０ ズ猛 ウイ,′ ０ 乃 為０ ０ ０ 表 1 検 体陽性数をもとに算定 した年間感染件数 Й ２０ ０ ０ ０ Ｐ ￨ ん０ ０ ０ ０ ０ つた。これ を年開発生数で表すと下記のようになる 優=D。 計算は、年間発生件数を用い て行 った。 〓 一 余の間に献血が原因と考えられる輸血後感染症は、HBV 95例 、HCV 3例 、HIV l例であ 1年間報告件数￨ HBV 898 HCV HIV 1 (1)HCV感 染 の Mar■c7連 鎖モデル ￨ HCV感 染後の患者は、急性肝炎→ キャリア■■慢性肝炎→肝硬変→肝細胞癌 とい う自然 推移 をとることが多いが、必ず しもそのょうな推移 をとるわけではなく、中には慢性肝炎 から肝硬変 を経ずに肝細胸癌を罹患するとい う症例も見 られ る。 また、肝硬変の症例は肝 細胞癌を合併す る前に死亡する例も見られることから、この推移は一義的ではない。 この ような疾患の自然推移をモデ リングするために HCV感 染者 の予後デ‐夕[1]、E2]、[3]、 :すi青 目の 本態か ら j番 目の状普 に推移 する確 率 (推移確 )を 意味す ぅ。 ￨￨で ヽp・ 警 点に慢性肝炎を発症す る確 子 を示 していぅ。 ■の推移行 例えば、p23はキヤ リアーが次 の時′ チ るもの 治綺す ることはな:く 角成分 よ りもヽ9攀 確素が全て 0六 、 患 ￨の `対 鷲 ′IFは 琴 1進 行 を仮 定 して、ヽる。 各時点で林鶏 が推移す ぅ確率が時点によらず 一定であ ぅ ことヽ ・ 上記のァル コフ連鎖モデルによ 't時 `点iに おiするそれ ぞれの状態の人数は、 現 を初期 レ,7連 鎖 モデルにお け 状撃の本数 ￨レ た とき、 Li三 ル,_lP=LOP′で表す ことができ、マィ のよ る推移行列を下記 うに定めることができる[11。 た とえば、1年 単位の推移行列を下記 のよ うに推定す ると、 0:00052 0 0 0 0 0977 0023 0 0 Markov連 鎖は別名 Markov過 程とも呼ばれる確率過程のことである。すなわち、未来の 0 0 0957 挙動が現在 の値だけで決定され、過去の挙動 と無関係であるとい う性質を持つ確率過程で 0 0 0 0923 0 0 0 0 0697 0 .0 0 0 ある。例えば、ある慢性肝^例 が肝硬変を発症する確率が、その症例がどのよ ラに (例え ばどの時点で)HCVに 感染 したかと無関係であるとき、この確率過程は MarkOV性 を有す るという。 上記は数式 により以下のように表すことができる。時点 iにおける集団の状態を、 003 0 0 ¶ ｍ一 酬 99948 E4]をもとに Markov連 鎖モデノ ンを用いて、NAT後 10年 間の遷移確率を計算1/、それぞれ の状態にお いて要する医療費を当てはめた。 0 0013 0 0,043 0,034 0303 1 'こ あ推 行列に対 して、初 したとき、年次の条件 期ネ件をL。子0 0 0 0 0 0)と 移 の推移は表 9、 10の 通 りであぅ。 ご?LIこ 夕時′ 態 、将来 の各病 の 数 ￨で 本 を代^す れ￨ゴ における HCVの 自然経過をモデル化できる。 l S,=61,2■ 3 ■4 ■5 ■6 ) . 、 2.輸 血後副作用颯告があったその他の感染症 とする。ここでベ ク トルの要素は疾患の推移 (HCV非感染、キャリアー、慢十 日千炎、肝硬変、 肝細胞癌、死亡)に それぞれ対応す る。次に、時点 1におけるそれぞれの状態の人数を、 L′ =014243444546) . とする。時点の経過 とともに、ベ ク トルの各要素である各状態の人数は変動する。マル コ フ連鎖モデルでは、 この変動を推移確率行列とい う行列で確率的に規定する。 , ` 日本赤十字社に報告があったその他の感染症として以下あヽのがある (表2)。 1についても年間肇生件数 もとに、「 直接 療費J「挙業堺本」ゃよび 「 早世￨こ 年 ￨￨:ら 「 i但し、「 レボウイルネB19」「 ヒトパィ よる遺失利益」の計算を行らた。 細菌」「 HEV」 による 感染は慢性化することなく、急性期で終息するものとした。 表 2 輸 血後副作用報告があったその他の感染症 ￨ (製 剤陽性例 1998∼ 20074F) 凛譜件数 糸田磋 百 感染者数/年 08(う ち死亡が 02) 梅毒 0 HTLV・ 1 0 ヒ トパルボ ウイルス B19 HEV 結果 : 1.直 接医療費 ー HBV、 事CV、 HIVお よびζの■の感響症の医療費は 「 ?005年 疾昼別医療費デ タ」(津 谷、2007年 )に より算定した。その結果を表 3(4、 5に示している。 平均在踪 日数およゞ平均外本日数1ま 患煮調査をもとに算定ぃ `?結 果1主麓ュL■ =旦 に示すとおりである。 さらにMarkリ モデルによる耳cVの 各病態今の遷移確率と予想される人夕を表 9、lo に示している。 ￨ とに計算すると 10年 後 直接医療費」it麦11に 示すょうに 間の 「 、今 ￨れ りをヽ 5 仮定としては、感染性因子低減化工程を取 り入れた場合 と取 り入れなかった場合を比較 して、取 り入れなかつた場合に 1年 間に血液製斉Jを輸血 され感染が成立 した患者群を 10年 間追跡 した場合の 「 直接医療費」 「 休業損失」および 「 早世による遺失利益」の総 コス トを 1こ 算定 し、 れを使益とした。 また、計算 の対象とした年齢は、わが国の標準的な動労者 とした。当該年齢の平均賃金 の厚 生労働省 の 「 社会辱療診療行為統計Jを 用いて算定 した。 ￨ ■者調査」、「 「 早世 による遺失利益」については、死亡 した時点か ら65歳 (収入が得 られる何 らかの 職業に従事 している上限年齢を66歳 に設定)ま でのFR5の 残奈年数を求め、昨今の経済情勢 をカロ 味 して賃金上昇はこの期間ない ものとして算定 した。 表3 肝 疾患の年間医療費 (津谷 2∞7年) ― 766,237 3,748.163 15,168,287 円 ,￨り 4う 【 17,310,343 慢性肝 炎 2,952,795 ll■ 破変 2,080,998 3,757,797 肝 細胞 がん 表4, HⅣ の年間医療費 (津谷 2007年 ) 11‐11 賜 法を採用 し、現在価値に置き換えた。ホ7● シ法については通常法定利.息(割引率)5%を 用い るところヽ昨今の情勢 に鑑み 3%と して計算 した (注 :参照)。 狭 :円 14,900,000 表0 そ の他の感染症 (細菌、 ヒトパルボ ウイルス B19お ょび ヨビリ の年間医療費 )麟 2007年 ) . 注)ホ フマ ン法 ` lやI入院:‐ Σ A/(1+nr)￨ n■ 1 円￨ 6,770,602 細 菌感 染 X:現 在価格 (手取額) A:将 来得 ることが可能な利益 n :利 益が生 じるまでの期間 r:禾U率 (割引率)3% (法 4,276,679 急性肝炎 これ ら3う の因子の今後 10年 間の値は、民事事件で損害額の算定に用いられるホフマン X〒 円 魯性肝炎 慢性肝炎 肝硬変 肝細胞がん ` ‐ 定利率である5%は 昨今の経済状況から用いなかつた。) 具体bll) X =2,945,00γ(1+OX0103)+2,945,000/(1+1ィ o o3) +2,945,000/(1+2X003)+ ・・・・・ ヒ トパ ル ボ ウイル ス B19 1,4431080 HEV 4276679 =外 来 ￨ 細菌感 染 ヒ トパルボ ウイルスB19 HEV 1円 ￨ 1,341,824 6,019,502 17310343 崎ｍ［ は、男女計 2945千 円(平均年齢は 411歳 )であらた。 , I 「 休業損失」については、入院の場合 1日 、外菜通院の場合 05日 の損失があらたものと 仮定 した。 2005年 疾患別医療費データ」(津容 2007年 )、平成 20年 .「 直接医療費」につぃては、「 242,987,846円 となり、1年当た224,298,785円 となる。 . 細菌感染については、「 その他の感染症および寄生虫症」 、ヒトパルボウイルスB19に ついては 「 皮膚及び粘膜の病変を伴うその他のウイルス疾患」 童Evに ついてはHⅣ 、 、 HCVと 同様に 「 ウイルス肝炎」の金額を用いた。 ￨ HEV感 染については、重症化することなく急性肝炎で終焉したと仮定した。 表 6 肝 疾患の平均在院 日数お よび平均外来日数 鳩 日 急性 肝 炎 量性肝炎 355 肝 硬 変 224 肝細胞がん 外来 肝硬 変 3617 500 440 ″千糸田胞 が ん 380 急性肝炎 慢性 肝 炎 表 7 HIVの 平均在院 日数 および平均外来 日数 ∞ 紡 日 細菌感染 ヒ トパ ル ボ ウイ ル ス B19 HEV `夕 ￨151こ 細菌 感 染 ヒ トノ'レ ボウイルス B19 233 ． ． ∞崎ヾ Ｈい∞ ”⇔ ︼ 表 8 入 院および外来期間 りＣ００黙 製Ｄ 外 HEV ゅ m H 卿 2.樹 失 今後 10年間の体業損失総計は、4,201,504円で 1年 当た り420,150円 となる。数が多い HBVに よる損失が、この過半 (2,751,410円)を 占めていた。 下するものと思われる。一方、今回の計算では 「 感染性因子低減化技術」を 1年 間実施 し た場合のHCVの 予後について 10年間のみしか考慮しなかった。HCVの 自然史経過は全体 で30年間程度に及ぶことから、 厳密には30年間の経済計算を行う必要があうたと考える。 ｀ しかし、30年 間の計算を行ちたとしても、もともとの感染予想者の数値が小さし ためその 増分は僅かであり、結果にはほとんど影響を及ぼさないことと思われる。 3。 早世による遺失利益 ‐ 過去に死亡例があつたり、死亡を想定 したものとして細菌感染とHCVが あるが、これ ら の結果を表 12に 示す。 図 1 都 内 の輸血状況 1 都 内の輸 血 状 況 1年 代別輸血状況(平成21年1月∼12月) ￨‐ HCVに よる遺失利益総計 0∼0量 21ヽ 10∼ 10歳 ￨ 2 0 ∼2 9 歳 3 0 ∼3 9 歳 歳 ９ ４ ”競 4.便 益 ´ : 以上より、不活化技術導入により得 られる 1年 当たりの 「 直接医療費」「 休業損失」「早 世による遺失利益」を併せた便益は、25.852.698円となる￨ (表13)。 腱 13 .不 活 イヒ技 術 導 入 に よ 目 傾本 (円) 243488785 4201504 101886690 258.526.979 25.852.698 ´ 考察 ￨ わが国では HBV感 染者が多いが、これは 「 直接医療費」 と 「 体業損失」の大半が HBV を原因としていることにも表れている。成人の HBV感 染の場合、その約 98%が急性肝炎 で 推移 し、ほとんど慢性化 しないことから 1年 目の医療費等の出費が増大するが、以後ほと んど影響を及ぼさない。但 し、近年の海外に起源を持つ HBVは 慢性化すると言われてい る がここでは考慮 しなかった。 ￨ HCVに ついては、慢性化する害J合が高いものの、HBVに 比人ると数が少ないことによ り、同様に経済的影響は少 ないものとなつている。 ￨ HIVに ついてもHBV及 び HCVに 比 して感染者自体が少ないことか ら、経済的影響は同 様に少ないものと考えられる。 休業損失や遺失利益は就業者を対象に したものであり、今回は勤労者の平均年齢を用い て便蓋を算定 した:東 京都 あ調査によると、輸血を受けている者の平均年齢は 646歳 と推 計 されることから、この平均年齢を用い ると 「 体業損失」と 「 遺失利益」はほとん ど生 じ ないことになる。加 えて原疾患の予後が不明であるが、健常人の生存曲線より減衰率が高 い ものと考えられる (図1)。 したがつて、 これ らのことを却味すると実際の便益は算定 し たものより少ないものと思われる。力日えて今回の計算では、輸血によらない原疾患による 輸血後の死亡のデー タがないため計算できなかったが、これ らを考慮すれば,層 便益は低 東 京都 輸 血 状 況 調 査 より l」暑 TML翻 の 薇 懺酉肇 島雉 五 鱚炉 馨 ぼ 雪 穏 馨 麗 燃 槽 。 級 中央値に年齢が集中していると仮定 して、輸血を受けた者の平均年齢を求めると 646歳 と推計される。 1 1 ま とめ 晨 1ゴ 去 、たっぃて111集糟で宗 した便基11較 しそ峯論する必墓:':;。 N鳥 はウイ′ レスを検出することに主眼を置いているが、ウイルス等の病原微生物そのものの不 餞こ 済 lど fF'層 斎 了 翼 野 墨 轟 ξ 聾 電 昇 す写 蠍 欄 Lヾ ア 錨 賃 ξ また、本稿では新興 。再興感染症の流行の問題を考慮していない`い かなる感染症まで 対象を広げて経済計算を行うべきか、そして血液の検査や製造ェ程にどの程度の経済資源 を投入す人さかについても議論￨｀ 必要であろう。. : : 参考文献 : 、 11〕 KenJi I■eda、 SatOshi Saitoh、 Iも ad Koida、 LsuJi Arase、 Ak■ hito Tsub6ta、 Kaをutt Chayama、 o Kttwahishi A Muitivariate Httomitsu Kumada and Masahむ Analysぉ ゞ Risk FactOrs for Hepatocenular carcttOgencsis: A Prospect市 e 卜ｍ Ｈ 爾 直接 医療費総計 休業損失総計 遺失利益総計 総合計 (今後 10年 間) 総合計 (1年 当た り) Observatlon of 795 Padents with VLal and Alc¨ ohC Cirr)。sis HepatO10g,こ 」uly:47‐ 53 [2〕 Yuli Kato、Keisuke Nakata、 不 attuhisa Omagari、 RyuJi Furukawa、 Yukio Kusamoto、 Iwao MOri、 Heiichiro TaJha、 HaJme Tanlokat MichitamiYano and s h i g e n O b u N a g a t a 1 0 R i s k o f H e p a t o c e n u l a r c a r c m O m a h r hP oa st i se n t s w i t h C む in JapanI Cancё r、 15(74112234‐ 2 238、 1994: :3〕KEN」 IIKEDA、 SATOSHI SAITOH、 ISAO KOIDA、 YASUJI ARASE、 ′口αHITO TSUBOTA、 KAZUAKI CHAヽ LttVIA、 HIROMITSU KUIIADA AND 1/1ASAHIRO Ъ bξ :[:規 漁講』 境ilttth犠 ::l]::::l:l::優 mttlstilIII::[i驚 C士rhoSis:Hepatolbgyt July:47‐ 53、19931 41 高瀬幸次郎、中野赳、為田靭彦、小坂義種.C型 慢性肝炎の予後に関連する因子の解 〔 ‐,析 :日本臨床、53:662・ 666、 1995 , ' 素熟、 lΨ熙就「猟勝獄∬ ぶiT犠 犠i濯穏 日館驚 批l嗜 F職 :∬ 鳳」蹴お よ 肺1ふ 星 ち 計認:l 翫騰)鵠r話 卜 ∫ 勝 れも :朧tneFttti“ m針 h晟 IVatd減 ma iSわ ぉ ad」 けlt露 ぃ.g宙 standard plasma Transfuslon( 39:479・ 487、 1999 ∞め Ｈ 質 問 義 : 置 一 ボ 診 問 以下の質問は、献血される方と輸血を受けられる方の安全を守るためにうかがうものですo 印 表現上、不快の念を抱か,る部分が●るかもしれませんが、「 何卒c 4解のほどよろしくお願いいたします。 責任あるぼ血」のためl_、 i , i t t ■i 申綺J I 彙 コ1 ( ■l r F 4 “ 雷と ■ぅ■音■■f ) 官■■■' , I [ ぢ J:￨ ￨■ ■ ■ ' 1 1 1 ス￨ ■ 1 1:￨::三 ■ 1 l f〕 _:ヨ l i 1 1 1■, ■ 露 ti'擦 き i ` ■沢妊 疑 , 「l r i t t : ′ I耳 躁蘇 万 = 嘉事事 ア 菫 ず 菫 嚢 F轟 認 謀【1翌■■華 IIP繭∵ T「市 確 1:llぎ 事百三 :翌 1で11笠 __■ lf」 =三二__二 11」 十 一 一 一 一 ― 一 ― ― ――― 十 一 一 ― 一 ― ― ― ‐ .隆 :薇 護蕊よ 落話 ξ農薦轟 百:赫 .Iき 簾 ふ ら 憶 菌 演 当 'し て 亀 間 以 内 で す フ :ゴ￨■輛 繭 荏 赫 I百 形 醗 黒輪0・ ・1 14F驚 職 蹴 誦 :愕 T´ イ :「 葺 電轍 響 季 黎量 事 =I=lT=￨ 劣 注 :〕 ζ 覆 『 麗「 寡藝墓 詰 労緊 ぶ ￨ネ ζ ￨:￨バ IF:￨ : 1■ :ち 1彎 登 I望 1‐ TttII:￨:11コ 目 11馨 :』蔚程■111 ニ ■ :11‐ :詳 弥 二 I 就 、 上萱翌1■1_[11lf■ ♂騒熙 く 19潮 i_三1印 ￨ .霧 聰訥IttL : ￢ ‐ ― ___― ― ―― ― ―― ―‐―――― ― 炎ウイルスの持続 染者 (キャリア)と 性的… 接触があつた。:_11_ _1 1ぢ [秀 、ぁるしヽ は境在治療中ですか。 ￨ ￨ 1 1 0ク 1 1 0軒 ぢ聰 聰 儡 儒 鵠 庸聯 、 i‖￨'株 ポ :櫻 蒻 の他 ( : : そ ‐ :な B型肝炎 がん(悪性腫瘍)、血液疾患:心臓病,脳卒中、てんかん ☆ 113r慈 も普ζ 季 聡病 膚管覗 3ァ ハ ( 注意) 1 2 生三ニ ― )● ご ￨"1葱1'首11ま専曇 裁 誉首孝1ジ … 睦や い 粁 俄副亀 ￨ ・― ヒ J三 ￨ ￨ ￨ ま IIJll ﹁ ●さ Ｆし ば 一 一 ドＬ ぐ [I:] :HI 「壼Ⅲ 録一 療一 診一 ＜一 献血 申込 書 Ｔ ︲上一 献血者 111査 」コー ド lと 弥 811炎ウイルス 〉、HIV 籠 炎 ウイル ス )、HCV(C型 献 血 した 血 液 につ いて、梅 毒 、HBV(B型 トTリ ンパ 球 向 性 ウイルスー1型 )等 の 検 査 が行 わ れ ること (エイ ズウ イルス).HTLV-1(ヒ を了解 し、献 血 します。 署 名 献 血 年 月日 品 秒皐憾 ri 1.萱「 鞘組暮 1l瓦は r3麟 ■■‐ .'「 て た f丁 i .Eし 唇えIし 政 正確間 を12扉 し ■ 献 血 され る方 は 、「は い い tヽえ 」欄 の 該 当 す る方 に 日■ また{よ=■ 印 を ご記 入 願 い ます。 それ 以外の 欄 に は、 問 診 を 行 う者 が、 必要 事 項 を 記 入 い た します。 採 血 センター 111 :占 ￨ まで i藪 あCt拓 ぶiこ該当 するこ とがあ りますか。 0イ ツフェルト ヤコカ高くC」 D)または類縁疾患と診断さねた。 ″ :ニ 菖 量 屏 [1悠 t鵡 :ヨ 量 hは Pttp亀 捧f■ 黎発 造‐ 三イ 二モ :■ _‐ :§ て 絨 鍼 緻 饒 i 11蒸 面 民[茨 あ属頁 事 =55ぢ :1_1こ 三 ジ 1量菱三主≡1五二 塵 [可 ` ￨ ‐ くだ さι 採血 (不採血)番 号 :〔コ 200fnt じl i 4 0 0 m L E コ 血板 ・ III口 ΠI I ・ 》 mケ■ ____■ ￨____」 重抒 ' 千駄 ′〕の 1 0 C ■t 敦 ` : J ￨ ￨ 1有 ﹂ 一 ﹂ ¨ ︲ ︲ ,一 ，一﹂・． ‐ 主 有 ,i ■ ¨ ， 薫 =' I ≒酢拳1準 由 無 こ ^￨ 適 1 薔 1 1 3 1_■____二 記 入例 : ‐ または ヨ 出 力記録 +跡 岬 20101( ‐ あⅢ Ⅲ讐■￨■￨■ 献 二 ■ 1黙車後の0知う●(検章■界) この予ラシをよくお読みいただき、内容を了承されたうえで、献血受付にお進みください。 anttただく 前に、 ています。(結果は詢血御 ケ月以内に親屁にてお届llし 書す) 検査結果通知のご希望の有無をおHttし Mお 願い:5 ( 1 ) お知 らせしてい る検査 項 目 ●血液型検 査 、生イヒ学検 査 0血 踪 針蠍 検査 C2)検査で異常を認めた場合にお知らせする項目 肝 ￨:癬 郡 献血 していただいた血液は、輸血や分画製剤性 して患者 さんの治療に用いられます。 患者さんが安心して輸血を受けられるように安全な献血をお願い します。 ￨ ￨ より安全な輸血医療 のために 薫‐ Ⅲ 肝氣`=主“饉葉"により育い世“に感染が拡がっています エイ ズウィルス(HⅣ)ゃ肝炎ゥィルス(IIBV、 との性交渉や、 注射器を共用し HCV)を 保有してい7.人 0渡 航歴について ・海外から帰口 (入国)し て相 間以内の方 、 ・昭和55年 (1980年)以 降=ヨー ロッパ ・サウジアラビアに 一定期間滞在 された方 (目名 ・期間等は受付におたずねくだきい) エ イズや肝炎のウイル不に聾 染 す る恐 れが あります。 麻 藁などを使 用した場合 に、 献 血いただけません。 下 記はいず れもこれらの危険性 が高い行 為です。過去 6ヵ 月以内に該 当する場合 !よ (a)不特定の具性または新たな興性との性的接触 (c)麻 楽、 ■せい相を使用した (b)男 性 ω方 :男性 との性 的機触 (`,C,∼ (c,饉当者との性的接傲 ・‐ ・ 集 饉・ ダい ‐ 0こ の3日間に出血を伴う歯科治僚 (抜歯 ・歯石除去等)を 受けられた方 工 存Cイ ルスや肝炎ウイルスの感染初期には、強い感染力を持つにも力ヽわ らず、最も鋭敏な検査方法 を用いても検出できない期間があり討 。 ￨ 0輸 血や臓器の移植を受けたことがある方 0ヒ ト出来プラセ ンタ注射薬を使用 したことがある方 二七珀麟葦漁燿出た■■￨=■￨■ ￨■li‐ : ‐ 0エ イズ感葉が不安で,エイズ検査 を豊けるための芳 エ イズ検 査 をご希 望 の 方 は 最 寄 りの 保 健 所 にお 「 . 5 合せ くだ さい 課 健 所 0 ま エ イズ 検査 を鷹 名 、 ‐ 「 (臨 鰯I嶽 席磐慇:1躍響 :麒 ・… 1‐ ・な 0こ の6ヵ月以内に下記に該当することがある方 ・不特定の異性または新たな異性との性的接触があった ・男性どうしの性的接触があつた 。麻薬、=覚せい剤を使用 した いるとわからた■合はご連絡ください. 歓 血後、健康診断 や医療機 関な どで B型 ・C型 肝炎の疑いがある と診断 された場合等 には、 嵐液セ ンター まで ご連 絡 くだ さしヽ (又 は主治 医に献彙 した 旨をお伝 えくだ さい) ・ 黎■1■ コけ￨● 11■ ■ ■■ .￨ ‐ ￨ 0梅 毒,o型 肝炎,マラリア・シヤーガス病詢 にかかったことがぁる方 ￨ D瀬 海驚鶴驚難器鑓群認そ 産裁警"°摯rす￨ ・輸血を受けられた患者さんについて、感染症などの報告があつた場合、輸血医療の安全性向上と 献血された方ご自身の健康管理のため、検査用ュ液の採血を再度お願￨・ する場合がありまち ・献血された方に「 輸血を受けられる患者さんのために」という印刷物をお渡しします。 楽 上記に腋当されない方でもヽ検診医の判断で像血を ご選慮していただくことがあります。 これ をよくお 読 み になって 、思 い 当 たる場 合 は、必 ず 献 血 当 日中 に血 液 センターヘ お 電 話 ください 。 ※ 医薬品 を組用 されている方1ま:必 ず検診医にお申 し出 くだ さい。 献血,F際して取得した皆様の個人情報は、血液センターにおいて厳重に管理されます。 +蟻 以下の内容をよくお読みになり、ご了承のうえ、献血申込書 (診療録)に _ E入ください。 :摯 n前に ￨ 献血後は、 本 分の補給と休憩 (少なくともlo分 以 上)をおとりくだoい 。 電車でお帰りの際、 転落防正のため駅のホームでは線路の近くで電車を待たないでく (気分不良、失神などはじうと立っていう時に発生しやすいといわれています) ‐ ■ お名 前 、生 年 月日、CL所 、電 話 番 号 等 は正 確 にお書 きください 。 の た め、運 転 免 許 証 などの 示 をぉ 願ル る :■ ,と が あります 。 甲 r本 人 ,確 認 警 。 ださ ●￨ 「"参影 質問にぃ正確にゃ奮えく ￨ : , ￨ 瑾一 献血後あ直ご砺 ￨ く献 血 当 日は次 の ようなことをお 願 いい たします > : ■プライ′,7■は巌守いたします. ■献血後に高所作業や激しいスポーツ、自動車の運転等をされる方は献血前にお知らせください。￨ 以上)を 取つていただく必要があります 特に乗り物の運転をされる方は、献血後に十分な休憩 (311分 ■副作用予防のため、 献血前に水分(スポーツい,ンタ等)を補綸してください。 水術0補 館1 1細 颯 ま : か ります 。 H20∞ 工 4∞ mL献 五 では lo分 か ら15分 位 、成 分 献 血 Clよ“ 分 か ら∞ 分 位 の採 血 時 閣 力勁 ヽ ■ 血圧 や ■色 素量 (ベモグロピン濃 ■ )を事 前 に測 定 します。 ジュース(スポー'ドリンタ)、 お茶などで十分補給してください ■ 採 血 針 は 、一 人 ず つ使 い 40て となって い ます 。 1聾 ■■作用と注意 . 日 採血に伴 う副作用が生 じることがあ ります。 採血中や採血後に、気分不良、吐き気、めましヽ 、失神な どが約0.9%(1/100人 )の 頻度で発症 し、 ことによう皮下出lllが まれに失神に伴う転●llが 発生することがあります。また、針をXllす ) の 剣贅で発生します`: )、 神経損傷 (脱力や痛み)が 細 01%(1/10,000人 約02%(1/5011人 口 絆鳳針 を刺 した箇 所 ■針跡力竣 るこ とがあ 2ま す。 口 」 と 塘詈 ￨:猛 響 を F歴F震 雫 島 拿 織 、 温 「 転 直ち 断護 ,捏 會た Tに 露:警 日採血中に気分不良やめまいを起こした場合は、直ちに職員にお知らせください,ま た、採血後に 同様の症状を起こした場合は転例を防止するために、すぐl=しゃがむか横になってください。 ・ 入 浴 … 2時 間 以 内 の 入 浴 と当 日の サウナ は避 け てください ・ 飲 酒 。喫 煙 … 献 血 直 後 は避 けてください ・ スポ ー ッは違 けてくださぃ スボ ‐ ツ :水 泳 、マラシンなど激 ししヽ ・ 重 労 働 一 採 血 側 の 腕 に強 い 力が か からない ようにお願 い します 日献血によって健康被告が生した場合に医療費等を補償する献血者健康被告救済制度が設けられています。 詳しくは血液センター職員にお尋ねください。 献=｀ しそいただぃた血液は ■ 献血血液は(医 療機 暉で血波を必要とする患者さんの もと、届けられ ￨す が、以下のよ うに 有効利用させていただくことがあ ります。 ・la液型や輸血副作用の検査 ・研究のため、薫血球型t白 血球型、血小板型及び血漿蛋百の 遺伝子検査を実施する場合があ ります. ￨ なお、その他の遺伝子検査をご本人の承諾 を行すに行 うことはありません。 ヽ 緊張感の強し 場合やその日の体調にようでは、 採血の数時間後、まれに気分が悪0つ たりめまいがすることが あります。 そのような場合はすぐにしゃがむか、横になつてく ださい。 通 常 は頭 を低 くしてЮ分 程度 安 静にす るだけで軽快 します 。 また、 採 血後 の 腕の痛み など何か ご心 配 なとき￨ま、 す ぐに菫液 セ ンタ=ま でご 出 肩 ください 。 ・血液製剤の品質管理や綸血用の検査試藻製造のために使用することがあります。 ・輸血の有用仏 安全性及び検査サービスの向上を目的とした研究のために血液を使用することが ありま丸 ○○○赤十宇血液 センター ()∝X‐Ю∝ =XЮ∝) : 口次の検査を実施し、血液製剤の基率に適さないと判断した場合は総こに使用しません。 . 移 イ'森 ｀ =督癬 ふ 用 を 彬 [1:ち り ズ ゑfttZ単 陥 3・ ξイ [ヨ 1輩栞̀′ 攘 鶴な 舅 Fツ 'り 動 採 Ⅲ 車の 運 行 予 定 や 献 血 ル ー ムのご案 内 な出 まホ■ ムベ ー ラで もご 覧 い た● ナます 。 wW“ QOOO OOO) (http:〃 ます。 口 血液の一部は少な くとも11年間冷凍保存 し、輸血副作IH・感染症な どの調査のために使jTlし 日 献 血血 波が採 血装置等の不 具 合 ・ 不 良により輸血に使用 できなくなることがあります￨ 140 OO赤 十字献血センター m XXκ 継 004博 鰤 センタ=― XXX‐― 献 血 ル ーム の こ案 内 ‐oo献 血ルこム メ X滲 Ю∝ XЮ∝ ・OO献 颯ル=ム Ю∝ XXX諄 ー… `OOmル 終 XXXX ・ 0鎌 血ルームxXX〉Ⅸ淮継 厚生労働省 “輛￨￨● イHrul,““瞑8お― o 資料 871 Press Release 平成 22年 11月 12日 医薬食品局血液対策課 (担当 ・ 内線)課 長 二 宅 (2900) 企画官 安日 (290コ) ( f t 表電 話) 0 3 ( 5 2 5 3 ) 1 1 1 1 0 望通 電 話 0 3 ( 3 5 9 5 ) 2 3 9 5 (F A X)03(3507)9064 報道関係者 各位 フ ィ ブ リノ ゲ ン製剤 納 入 先 医療 機 関 の追 加 調査 につ いて 平成 16年 12月 9日 に公表 した フィブリノゲン製剤納入先医療機関を対象として、 平成 19年 11月 7日 付で実施 した追加調査の結果11ついて、平成 22年 10月 1日 ま 二 に回収 した医療機関からの回答 を取 りまとめた状況をお知らせいた します。 (1)追 加調査実施期間 (1)投 与の年月について回答があつた医療機関数と元患者数 医療機関数 元患者数 9125施 設 ￢3 , 7 3 8 人 ( 投 与年別 は別 表 ) ( 2 ) 上 記以外にt 過 去に投与の事実をお知 らせ したという記録が残されているが、現 在 1 ´では投与の年月は特定できないとする回答があうた医療機関数と元患者数 医療機関数 元患者数 (3)(1)と 95施 設 312人 .(2)の 合計 医療機関数 元患者数 1,001施 設 (※2) 14, 050人 (※2)厚 生労働省ホームベージ 「C型 肝炎ウイルス検査受診の呼びかけ (フィプリノゲン について)」 の公表:医 入先医療機関名の再/AN表 製lll納 療機関等 リス ト上の該当医療機 ‐ 関 の 「 備考J欄 に、 「 フイプリノゲン製剤を投与されたことが判明 した元患者の方が いるとの報告あり。」と記載 した。 平 成 19年 ￢￢月7日 ん 12月 5日 (※1' (ただ し、現在も回収中) (4)元 患者 の方 へ の 投与 の事実の お知 らせ の状況 「 (※1)・(1)の 調査以降、平成20年 8月 25日 及び平成2￢年1月 16日 にも元患者の 方へのお知らせ状況等について再度調査を行つており、 ( 3 ) 回 答施設数以降はそれ らの結果を反映したものである。 ￨ お知 らせ した 81 116人 (58%)(※ お知 らせ して いない 5, 934人 (42%) ( 2 ) 追 加調査対象施設数 療機関 6 , 6 1 0 施 医 設 ( 平成 1 6 年 公表施設の うち、所在地等が不明であつた施設を除いた医療機関) 投与後に原疾患等により死亡 1, 974人 (140/6) 連絡先が不明文は連絡がつかない 21 755人 (20%) 肝炎ウイルス検査の結果が陰性 422人 (3%) ( 3 ) 回 答施設数 ・ 平 成 1 6 年 公表時に存続 していた 5 , 3 9 7 施 設の うち、5 , 2 9 1 施 設 (98%) か ら回答があつた。 ・ な お、このほか 平成 1 6 年 公表 時 に廃院等 していた 1 , 7 ￢ 3 施 設の うち、5 0 7 今後お知 らせする予定である 228人 (2%) 555人 (4%) 施設が ら回答が あった。 その他 (未記入含む) 14,05し 3) 0人 (※3)元 患者の方に■人でも投与の事実をお知らせした医療機関は827施 設であった。 Ｈ¶ Ｈ 1 回 答状況 2 主 な調査結果 ( 別表) 投与の年月について回答があつた元患者数の投与年別の内訳 ( 5 ) 診 療録等の保管状況 平成 6 年 以前の診療録等が次のいずれかにより保管されている施設数 手術記録あるいは分娩記録 1, 498施 設 (23%) 設 (24%) 1, 576施 製剤使用簿 処方箋 輸液箋あるいは注射指示箋 崚セ プ トの写 し . 入 院サ マ リー あるいは退院サ マ リー その他 の書類 ０ ７ 2 , 0 4 ￢ 施設 ( 0 1/° o)(※ 4) ( 内訳) ( ※ 5 ) 診療録 ( カルテ) 人数 投与年 昭和 39年 135施 142施 277施 設 (2%) 設 (2%) 設 (40//o) 83施 設 (1%) 291施 295施 設 (4%) 設 (5%) 8人 12人 42年 143年 ￢6人 118人 44年 45年 19人 46年 22人 47年 25人 48年 34人 49年 48人 48人 1 50年 51年 6.7人 52年 88人 53年 128人 の設間であつたため、保管していると回答した施設の割合が異なつたものと思われる: 54年 198人 55年 3‐ 22人 (※5)厚 生労働省ホームベージ 「C型 肝炎ウイルス検査受診の呼びか￨チ(フィプリノゲン 製剤納入先医療機関名の再公表について)」 の公表医療機関等リス ト上の 「 ヵルテ等 の有無」欄に、平成6年以前のカルテ等の記録が一部でも保管されている場合、△印 56年 431人 を付していたが、さらに保管されている記録の保管期間、保管状況等を記載 した:‐ 57年 564人 58年 963人 487人 59年 60年 1 716人 61年 2 379人 62年 2 913人 63年 1 686人 平成 元 年 206人 2年 157人 3年 91人 4年 43人 5年 219人 6年 13人 計 13, 738人 ＮヾＨ (※4)平 成 16年 の調査では 「 昭和 63年 6月 30日 以前にフィプリノゲン製剤を投与し 対し、 た記録 (診療録、使用簿など)が 保管されていますか,」 ￨の 設間で■づたのI子 今回の調査では、 「 干成6年 以前のカルテ等の各種書類が保管されていますか。」と 40年 ■ 41年 人 人 (括弧内は調査対象施設数に対する割合) ●鱗撫 厚生労働省 資料 8-2 口' 露 町 J H ●l h i 轟 Press “ W嚇 Press Release 平成22年 10月 27日 医薬食品局血液対策課 (担当・ 内線)企 画官 安田 (2901) 課長補佐 難波江 (2905) (lt表 1雹:活)03(5253)コ ￢11 (直通 電 話 )03(3595)2395 (F A X). 03(3507)9004 平成 2 2 年 1 0 月 2 5 日 ( 月) 医薬食 品局総務課医薬品副作用被 害対策室 室長補佐 : 信 沢 ( 内 線 ) 2 7 1 7 管理係長 : 内 沼 ( 内 線 ) 2 7 1 8 ( 直通) 0 3 - 3 5 9 5 - 2 4 0 o 報道関係者 各位 C型 肝炎訴 訟の和解 につ ぃて 本日、名古屋地方裁判所において、下記のとお り和解が成立 しま したのでtお 知ら せ します: ヽ 平成20年 1月 以降、同地裁に係属 している原告 (患者数 2人 )に ついての和解。 ‐ 「 製剤はフィブリノ￨ゲン製剤。 (参考) . 1 趣 旨 ‐ 1 ‐ 7イ ラ'ノ グ摯 剤1納 入が確認されをぃる厚年労働省岳管あ医療機茜及 び国立大学法人の医療機関1こ対し、 診療録等あ保管状況を確認するとともにこ 投与事実の確認作業の実態等をIE握するため、今年度は、然下の要領で訪問 調査を実施する。 1 、 ■ 2 調 査対象施設 ‐ ‐ ラィブリィゲン製剤の納入実績等をPHkま えて選定したo4医 療機関 (別添参照) ￨ l r l . 1 1606人 0和 解等成立人数挙 O新 規提訴等人数※2 1764人 ‐ ￨ (10月 22日 現在) , ※i「和解等成立人数」は:今 回の和解成立者は含まず、これまでに和解が成立 した人数 (患 者数)で ある。また、調停が成立した4人 を含む。 ※2「新規提訴等人数」はt救 済法施行後に提訴等し、訴状等が国に送達された人数 (患者 数)で ある。このうち、1398人 は既に和解等が成立している。 ￨ 3 調 査のスヶジュニル ■ 年度内を自途に訪間調査の結果をとりまとめt公 表を各ら予定` (参 考) 1 1 1 : t フィプリノゲン製剤の紳入が確認されている厚生労働省所管の医療機関人の訪問調査は、■成2o 年度に4o病 院、平成21年 度に 16病 院実施済みである: ｍヾ ［ 上記の症状の内訳は、肝がん 1人 、無症候性キャリア 1人 である。 ‐ (別 添 ) ○調査対象施設 (4):l■ 会堡険中琴総合病貯 ￨ ‐ 1.(独 )国 立病院機構病院 (1)北 海道がんセ ンター (5)社 (6)社 (7)社 (8)佐 (9)社 (2)函 館病院 (3)高 崎総合医療セ ンタニ (4)西 埼玉中央病院 ￨ ・ ‐ ‐ (5)名 古屋医療セ ンタ (6)京 都医療センター ￨ l (7)神 戸医療センター (8)姫 路医療セ ンター 、 (11:)都 城病院 21(独 )国立高度専門医療研究センター (1)国 立がん研究センタニ 中央病院 (2)国 立国際医療研究センター病院 :3.労 災病院 (1)中 部労災病院 ￨● (2)神 戸労災病院 :￨￨(3)中 国労災病院 (4)山 口労災病院 : t 会保険京都病院 会保険神戸中央病院 会保険下関厚生病院 ■ 賀社会保険病院 会保険宮崎江南病院 5.国 立大学附属病院 (1)東 京医科歯科木学医学部附属病院 (2)東 京大学医学部附属病院 .(3):東 京大学医科学研究所附属病院 (4)神 戸大学医学部附属病院 .(5)山 口大学医学部附属病院 : (6)佐 賀大学医学部附属病院 (7)宮 崎大学医学部附属病院 ‐ (3)鹿 児島大学病院 : ヾヾ ［ (9)兵 庫青野原病院 (￢0)呉 医療センタ= 4.社 会保険病院 . : (1).札幌社会保険総合病院 (2)北 海道社会保険病院 (3:)社会保険船橋申央病院
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