EB病毒感染相关的噬血细胞性淋巴组织细胞增生症的免疫化学治疗进展

EB病毒感染相关的噬血细胞性淋巴组织细胞增生症的免疫化学治疗进展 EB病毒感染相关的噬血细胞性淋巴组织细 胞增生症的免疫化学治疗进展 2003??10?k?c5???c5?T ???????J ??x?nnr?? kle} EB?????T???????????U?????h???????????????T?????q???V?????????? ??????R??????xR?(???D????x??_?_????x?210002) [????????sB???YHLH-94???>??EB?????T???????????U?????h???????????????T??(EBV-H LH)????????x????3???????E?q???V???????>???s???? ????s0?/?3???????s(VP16)?????T(?????(4????)??????(?A4????)4xp?u??)???ms0?????:??x???? N???????????????HVP16???????????/?G?T?? ??x??l?????????????)x{s0???l?????h?u???????m???:??xI???3????((IVIG)???c?????>?l???Ea x??????:?????h?_???hEBV?T??(CAEBV)???>s0?????h EBV-HLH?VCAEBV?????m?G?????k?V???E?G?V?:?U?????????B(HSCT)s0??x????lHSCT???h?G??EBV-HLH?????q???V?????????l?>?-???????E?? ???(?K??s0 s9??????sBEB???????U?????h???????????????T???q???V?????? xy???n????:8551.2;R453???t?r???2:A?????V??:1672-271X(2003)05-0390-03 ?+?????T????s2???D???hs2?D?????6??xl???U??s2???????? ???U?????U???????H?i???U?????h???????????????T?? (hemophagocyticlymphohistiocytosis,HLH)????????x????? ?.sE:Ix?:Is4s0?m???????F????x????????????????hs2?????h?????h???? xy?E?????????????????????????”??????s2xy??????????????x? ?????????U??????x??T?G??????????I?]aHLH?5???????h(???? ?h)???????h(?T?????????R????)????I”],EBV-HLH?nx/4 ??????????191:1?????T???????:???h???F???????G??((IM)?? ??EBV-HLH;II???m?l????????IM?d?????????5?????_???? ?????E????EBV-HLH?????????};I???mCAEBV??x?xyEBV- HLH??x/x????????hx?x??V???g?hx?x????T;N???m?V??T?? ???????R???5????x/EBV-HLH????????????s0?????h???????F ??x??????hHLHs0??????????????HLH?E?R???i?????hEBV- HLHxB??????[[1-s7s0???,EBV-HLH???????????E???g?i?q???V ????????????x”??????????x}????s0 1x”???????????? 1.1????HLH?i???U???????k??(hemophagocyticsyn- drome,HPS)??????(prototype)?E?m?+???????Gx?HLHx??? HPS?????-[:6s4s01979??Risdall???>????????EB?????i?4?? HPS??x_?????????:[[3]s0?h?G??EBV-HIH????????x??l?(?D ?q???????/?????+???V???H??[[1”eEBV-HLHx??????T?m?:?? ?h???F???????G??((IM)s2???h?_???hEBV?T??(CAEBV)s2???? ?hHI.H(FHL),X???????????h????(XLP),?????????h?????d ?V??T?????R??NK???????U??????x?[3,6,11.12]s0??x/EBV-HLH ?????m???????????????E???N?,EBV?T??????????T???? (CTL)??NK?????4??????????????(cytokinestorm)?E?5???5 ?gEBV?????????v???????????E?Y?[x/x??????????????? ??[?Ex?5,81s0 1.2?%?w?????????F???T?m???cs2xy??(?g????)????x?x??? ???????+???????H??[[16[?E?z????????x????l????.3]s0?m???c?? ???l51.7???+?????THLH?E???b??x(EBV?????E?Y???c?+?? EBV-HLH???T?????H????25??[3]s0????????????1x?2???E?d/ ????x/s0.64?E?????-??????[[3]s0?????hHLH????????????xy??6 xp?k?Ex(EBV-HI_Hxy??6???D??xB?Es0 R????????E?d?E194s0???T?E???????8x??E?h???c???Ex_x??_?ks0?9 ???H:?U?????Rs2???Ux(?U?-??x”????????????????s0 R????D???c532?_??????????????242700 x?390x? 1.3?????/?nEBV-HLH???????/?n?GxB?%?n?5???E?T?? EBV??T?????????i??????x_??????s0?G?F??x/EBV?T??B?? ????????????T?????G?v???????E?????D?????????E?/???????? ?????????????????????S???wx/s91-6?81.EBVx???????????T?? ???????????D?????????E?????????:((IFN)?????R???????? (TNF)?iHLH?D????????????xy???/?N[16.81s0?/???0?F???h ????????????(LGLs)(CTL/NK????)?????E?4?????????????U ???E?????1???)???????E????????????s0x????????????U??x/xy ???/?N??????:R?xy?h?????????H?E?/?G?T??;R????U???T?E???U ?????E?4???????h???U;R???s2??s2???{?G?)??????(MOFP-s,?Ja 1.4????EBV-HLH?????r??x/:R?????????1???E????) 38.5C;R????D???h?”???U???????H(?i????2xp???????E?????? ?T???x?V???T?0?F);R????????0?F(?ULDH?????F?=?O+3SD, x??c)1OOOU/l.)?????U????????(?U???????????r1.5g/L), ?”?????????U??(?????F?O+3SD?Ex??c?x1OOOng/ml);R????U ?????????????????=?l?F????)3%?V(??)?i??????s2??????s2 ??s2?D??xy??????????????????????;R??U?5?????????vEBV?? ??????(VCA)-IgM?V??G?????]?h???/???????V?>?q?l???? ??????s0???T????(EADR)-IgG?VIgA?????]?h???/?????B?_s0 ?n???T???????i(?5??????PCR,Southern?n???????q?ux?)?? ?v?U?5s2????s2???????{?r?c???mEBV??????DNAs0????PCR?v EBV?????????A???E???q?ux????v??EBV?V?2??RNAa 2?q???V??????????x_???????E ??x????????????U?????????????9???i?_?????h????(cas- cade)?E?????Ox??????h???????????k??(systemicinflammatory responsesyndrome,SIRS)???????E?(?5x????,???????????4?? MOFE3ls0x/x????N???5???T??EBV??T/NK???????0?F?_?V?? ?????????E???m?q?????N?u(???????m???:s2?????:s2???????3?? ??ATG?V???l????xI???3????IVIG)????????????(???????s VP16???G?????k?V??)[??6,8.13] 2.1???????????l??????xV[[5]?K???????????nHPS?????n x/xlxp?N??:????HPS????x/?x??s2???U???????H?E???????????E ?????????V???m???O???VIVIG;xy??HPS??x(????HPSxv??) ?????q???V?????????N?_?V??T??????????????;????HPS?? ?5?l?????????U???????Hs2???????0?Fs2?7???h?U???????U (DIC)s2?U?5????????x????,?.???D??????s2???????????E???q?? ?V?????????????E?I?????G?????k?V???V?:?U?????????Bs0 Imashuku?nEBV-HLH???????????nx/xlxp????[]:Cs4:R??? 2003??10?k?c5???c5?T ?N???????????E?5?????U??????MOF;R????N?/?G?h?T??;R??G ???q???V???U???v?????????T??EBV??T/NK?????E?????h?? ???V????????CAEBV?????????m?G?????k?V???V?:?U?????? ???Bs0 2.2???N?????????????N???5???T??EBV??s2??????T/ NK?????E???N???????????U???i?J????x??T?????cx? ??[[3,8.13,16]s0?U?z????((PE)?Vx??????U((ET)?E?V???m?????m???: ?F??x/?cx???????????????s0??????x7?????A?T???????????? ?:???????m???:?l??x?????????[31 ???YHLH-94???>?:?????m?g???????s(VP16)?????Y HLH-94???>[[8.17s4????EBV-HLH?Ex??5????????T/NK?????? ?_?V??????????????s0?????>x????m??????FHL????x?HLH ???5[171s0???m???????s???m???h?u???s?????????w8???????? ????s0?m??x/:???????s150mg/(m2.d),2/??X2??;150mg/ (m?.d),1/??X6??s0?s??????IOmg/(m2.d)X2???E5mg/(m?. d)X2???E?[?[????4??s0?????:x_???mx?xy?h?????????H???? ???E???????T?/?G?T??[[31?????N???????????U??[[7.3.8.16 s4?V?? ??/?B????????[l1s0x?1-3mg/(kg”d),24?)???????E5-7?os0I- mashuku????17??EBV-HIx?H???5??HLH-94???>?????(5?? (29%)?????-???E10??(57Yo)???????2?????q?????2?-???? ?2?E8???(???n?-???5x??s???????????????E???????m?????:?E ???????sx???2?8181,2?????>??x??0???????????Bs0????14/17 ??(8200)?q???V???????5???2?????-??????4+-39+?k(xy?? 15+?k)?E???/???????(?B?????????h???xs0??x/??x??h?G???p ??BMT?VHSCT??EBV-HLH???5?E???m?????m???:???????? ?s?V/???q???3???u?????s?l?>???N[[81 Imashuku????47??EBV-HLH???5(?h???nx/xy????x?x7 ????)???5?gVP16???q???V???(4???T?????D??????(78.30o ??6.700)[„“.VP16??x??????(4??xv???????5????4???(???? ?V?p?mVP16???5???E???T?T?????????h?n?gx/(40.9%?? 10.500)?9sB??(57.2%??6.200)[z01,PG0.01s0x?????4???????? VP160-3xp?u????7/1s0????x??E?E????4 xp?u???????? x?(0/33??)?E?q????x????D??x/??(P=O.0001)?E???/VP16?? ?T(?????(4??xv??)s2????(>}4xp?u??//4????)?l???????? ?([[181s0???T???m?????:?p???T?????h?/?G?T??(0/10??)?E?p?m ?V?????m?????:16/20?????T?????h?/?G?T???E??x/???T???m ?????:??????VP16???????????????h?/?G?T???V?????????? ????xy?h?????????H?O????x????9?????s[0181s0???n?????A?T?? ?m?????m???:?V?h?u???????O????(lg/dX3?8)???????Ex??2 ???????????????r?rxB?K???Ex??(?h?G???mVP16?(???????? ????[[31s0?zVP16???m??xB????????????xy?h?????????H???? ???/?G?T??????xv?V{[1,3,8,16,171?E???T?V???B???m?????TVP16 ???????7?h???h???U??(AML?d,181?E?YImashuku?r???????? ?T???m?gVP16???>???????????h?E?i?X???d????????x?EBV- HLH???5???q?????E?V?5????x?xy?{????x7??????x??l???? ??s0??x????????????????m?q???3???u?E?,?7?(???mHLH-94?? ?>?O???3??[[18]s0x/x??7??VP16?4???2??xy?h?????????H??xB ???????E????xV?{?????)??VP16(?F?m??150mg/m2??112-1/ 3??)?D?/?D???????>Cs; 2.3??x??l???h?q???3???u???l?????h?u??xI???3???? 400mg/(kg.d)X3-5d;ATG(??)10mg/(kg.d)X5d;?o?????? (?s?????????????????ELimethasone)4mg,3/??X2??[3.177s0 x”?????m?????E?????m???:??/?VIVIG????x????N???????K?? ????[[3]s0x??l??x/IV??G?>???l??[3]?Vx??????-??[[l8]?E?????N?? ?????????U??xB?p?l?>[[3]?E?G???l??(?????N?u???g?l?????? ??))[37s0xB?mIVIGxB?G???????>[3]?Ex??l????x???x”??????s0?? ?V?E??????CAEBV??x????max??????:???>[2l[s0???mIL-2?????N EBV?T???l?>?E?zx??l???????????0?F?2?????m[[a3} 2.4?????????????i?2???????h???9???E????(?x??)EBV- HLH???5???m?+?9?a???V???9?a???p???D?/?????????m[[3)s0??x? ???????????U???4???????U???E?m???mx7?????U?D?H????x?PE/ ET?i?l?>???E???????????????U?z((FFP)[„“,a?s0?????m???????? ?N?u?E?????????N????x?(nafamostatmesilate,Futhan)s2?????? ???A??(Camostatmesilate,FOY);?V?K?h?????????N?u?+???? x?x2(urinastatin,Miraclid)s0??MOF???U?z?????U??I(ATI) ?”???(?D???x?E???l????ATI???????U?z???U?????”??[Ue7 2.5?????h???????????h?????????hEBV-HLH???r?? x/[[3]R????5?gVP16?q???V?????>??????;R???EBV?????U?5 ??????(VCA-IgG>1280,EADR-IgG>320);R?NK????x??? ??(?mPBMCxy>400o);R??2????????EBV?????????A??s0?? ?????????????mATGI?l?Ex??????m???????B?=???????R?V?B?= ?????????k?V?????>?E??CHOP,ACDOP(A?+?l?:,PxI???? ?[)???>?VABVD(B?????l?:s2D????????)???>[[I,3,8]?E?V???m ?h?u???+?????9s2?V??????????????(L-ASP)”„S]?E??Capizzi (Ara-C3g/m2X4?EL-ASP10OOOU/m2X1?EPSL30mg/maX2)?E ?V?h?u??Ara-C(Ara-Cl.5g/m2X12,PSL30mg/m2X6)”„?E?V ?????:?U?????????B[Li3,5.81 3?????h???????? ???3Slobod?{?????”EBV???????????hCNS?????R?? AIDS???5???m?)?u???????l?l?>s0?????????n?????Ux/?)?u ???????l???5??x????R???????????????V??DNA?dEBV?F?? ????s0???????m?)?u???????l(400-700mg/m?.dX48??)?E ????????x???EBV???????????R??EBV-HLH???l?>?h???? x???????[2:]s04???? ???????h??60%??EBV-HI.H???545??????x?CAEBV, ??x?????x_??x/????s2????s2?1?????????????????h?????? HPS”“051??EBV-HLH????x???410o(21??)?E?,x?xy?h???? ?????H?????????V/???l???T??[“eImashukuE?8s4????47??EBV- HLH??x????q???V???(??4???T????x/(78.3%??6.70o) (SE)s0???U?5?”????????s2LDHs2?????hIL-2R??IFN-Y?=???/ HLH??x??B?????????h????[4,11oImashuku?r??CRP>lOmg/ dl??EBV-HLH???5?b??x?xe???T??x?E221 ???3???t [1]ImashukuS.Advancesinthemanagementofhemophagocyticlym- phohistiocytosis[J].IntJHematol,2000,72:1 x?21TakahashiN,ChubachiA,KumeM,etal.AclinicalanalysisofS2 adultpatientswithhemophagocyticsyndrome:theprognosticsig- nificanceoftheunderlyingdiseases[J].IntJHemato1,2001?E74: 209 x?3??ImashukuS.ClinicalfeaturesandtreatmentstrategriesofEpstein- Barrvirus-associatedhemophagocyticlymphohistiocytosisx?J7. OncologyHematology,2002,44:259 [4s4???????E???o??.???U???????k???9??????[J].???V?_?????U?? ?U?????n???E1998,21:353 [5s4????xV.?U?3?p????????[Jl.x”???U???E2003,44:1 x?391x? 2003??10?k?c5???c5?T [6??ImashukuS.Differentialdiagnosisofhemophagocyticsyndrome: underlyingdisordersandselectionofthemosteffectivetreatment [J].IntJHematol?E1997,66:135 [7??CohenJI.Epstein-Barrvirusinfectionx?J].NEnglJMed,2000, 343(7):481 [8]ImashukuS,HibiS,OharaT,etal.EffectivecontrolofEpstein- Barrvirus-relatedhemophagocyticlymphohistiocytosiswithim- munochemotherapy[J].Blood,1999,93:1869 [9??ImashukuS,IkushimaS,HibiS,etal.Langerhanscellhistiocyto- sisandhemophagocyticsnydromeinJapan;epidemiologicalstudies [J].IntPediatrHematol/Oncol,1994,1:241 [10]TakahashiS,TabataY,TeramuraT,etal.Lymphoma-associat- EdhemophagocyticsyndromeinJapanx?J].Jpn]ClinHematol, 1999,40:542x?549 [11]HondaK,KaneganeH,EguchiM,etal.LargedeletionoftheX- linkedlymphoproliferativediseasegenedetectedbyfluorescence insituhybridization[J].AmJHemato1,2000,64:128 x?12]IshiiE,KimuraN,KatoK,etal.ClonalchangeofinfiltratingT- cellsinchildrenwithfamilialhemophagocyticlymphohistio- cytosis:possibleassociationwithEpstein-Barrvirusinfection[J]. Cancer,1999,85:1636 [13]EakleJF,BressoudPF.HemophagocyticsyndromefollowingEp- stein-Barrvirusinfection:acasereportandliteraturereview[J]. JKyMedAssoc,2000,98:161 [14]ImashukuS,HibiS,TodoS,etal.Allogeneichematopoieticstem celltransplantationforpatientswithhemophagocyticsyndrome (HPS)inJapan[J].BoneMarrowTransplant,1999,23:569 [15??TheHLHstudygroupofthehistiocytesociety,HenterJI,Elin- derG,OstA.Diagnosticguidelinesforhemophagocyticlympho- histiocytosis.TheHLHstudygroupofthehistiocytesocietyx?J]. SeminOnco1,1991,18:29 [16]ImashukuS,TabataY,TeramuraT,etal.Treatmentstrategies forEpstein-Barrvirus-associatedhemophagocyticlymphohistio- cytosis(EBV-HLH)[J].LeukLymphoma,2000,39:37 [17]HenterJI,AricoM,EgelerRM,etal.HLH-94:atreatmentpro- tocolforhemophagocyticlymphohistiocytosis[J??.MedPediatr Oncol.1997,28:342 [18]ImashukuS,KuriyamaK,TeramuraT,etal.Requirementfore- toposideinthetreatmentofEpstein-Barrvirus-associated hemophagocyticlymphohistiocytosis[Jx?.JClinOncol,2001?E19: 2665 [19]ChenJS,LinKH,LinDT,etal.Longitudinalobservationand outcomeofnon-familialchildhoodhaemophagocyticsyndrome receivingetoposide-containingregimensx?J].BrJHaematol, 1998,103:756 [20]ImashukuS,HibiS,TodoS,etal.Hemophagocyticlymphohistio- cytosisininfancyandchildhood[J].JPediatr,1997,130:352 [21]OkamuraTHatsukawaY,AuaiH,etal.Bloodstem-celltrans- plantationforchronicactiveEpstein-Barrviruswithlymphopro- liferationx?J].Lancet,2000,356:223 [22]ChodoshJ,HoldenVP,GanYJ,etal.EradicationoflatentEp- stein-Barrvirusbyhydroxyureaaltersthegrowth-transformed cellphenotype[J].JInfectDis,1998,177:194 (?N?+2003-07-07) (?c???V????????) ???+??????????x(???a ???y??R?????(???D???c95?_?????????????s351100) sE???t??s4???+?????????? xy???n????:R587.1???t?r???2:A?????V??:1672-271X(2003)05-0392-04 ?mxV?w???G?????E???+????x??%?w?????T???-???ExV?w???T ????????:?s2025?????+???????????n??3?B?E???+???n?[x/?? ?f??xV?w??x”????x_?????T?H?6xvx?[[11s0?h??x??????(?E?????i ???+?????????????????t?U?ms0???m1993???E???+?????Nx(?? ????????(DCCT)???(?E?S?????+???????E???????5x_???q?k?E?i ???s???????N???q??s01996?????Y???+??????((IDF)???i?n?? ?+???????Px/???+??5?????c????????xvx?s0???????ExV?w?1?? ?????+?????????w?G????s2?????q???????9?????????????ExB?? ???????????E????????x}s0 1???+?????????? 1.1???5???_??x????m???+??????xy???s?q?l???5x_?:?? ?3?=???/?3???5??x??h???????E?????m???+??????xy???9???? ?????????E?????+?????H???n?????;x??E?ExB?i?w?????????? ???E???d?l??x??_???????m???{s2???????k????????x}???w???+ ????????s0?E?_?Tx/???5?????????h?????E???????????L?????? ?;x??E??????x(?s???+?????????????}xy?E?t?????5x????????? ?????????E?:??????x-xG?????E????x/???2???????T?_?m???E?? R????y???E???E1955???T?E1980????xGx??cx????_?h???_?????E x_x??_?ks0?9???H:???n?????+???????9??s0 ?????????????????E?????q?kx????[????[[3.4]s0?m???+??????xy?E ???nx??????G?sx/???5?????????l???7??s2????s2?_?????????? ???{x??c?h?????+???????????E?????????5????s2?+??????s2?? ?V?U???????O?{?E?????mxB????????s0?l?9?????(?E???G?????+?? ??????x??G?????u?k???[?Ex?x??h?G?????????U?????5???? (52%)?E?E??xy?{(26%)?V???????????5????(27%)?Ex?x????? ???2???????+?????i????s2???/?U?????Ns2???????5???????+?? ????s2x/???????5?????????{???????l?D?????????m[s7 1.2???+????????x??.???N?????????????? 1.2.1???+????????x??.???N???????G???9?????(?E???5?? ?+???????”??????????x??.???N?K???l???????ms02?????+???? ?5?G???????E???/???????Ns2?????_???????H???v?{?wx/?3???E ???????U??s2?[?(2?)???U??s2???V?U?????????s?(?D?K??s0x??? ????????????????s2?????h/?{x?65??s22?????+?????h/?{x?1 ?????2??x????w???U?????0?????7???????9?????(?E?G???7?? ??????????x?x???x??.???N?”???E???s?U?????N???????r???Ex( ???????????E???????????U???????V?U???????D???K???E???G?? x????s?_?????????N???r[77s0x?????53?B13 ??1?????+?? ???5???w??x/?T6?????9?????(?E???+?????????K??x?x???x??. ???N?E?G???????????+???l?????????????????????E?????F?s?? 392