噬血细胞综合症2例并文献复习作者杨宝忠.ppt

噬血细胞综合症,hemophagocyticsyndrome2例报告并最新文献复习,杨保忠执笔2011-11-9,病例1：女性，22岁。间断发热伴关节痛、皮疹28天入院。查体：T：38.1,P：88次/分，R：18次/分，BP：100/60mmHg。神清语利，查体合作。全身皮肤黏膜未见黄染、蜘蛛痣及瘀点瘀斑，颈部两侧可触及皮下结节，活动度可，无压痛。眼结膜无充血、苍白，巩膜无黄染。颈静脉无怒张，双肺呼吸音清，未闻及干湿性啰音。心音有力，心率88次/分，律齐，各瓣膜未闻及病理性杂音。腹平，未见腹壁静脉曲张，未见胃肠型蠕动波；腹软，无压痛、反跳痛及肌紧张，肝脾未触及明显肿大，Murphy征阴性；肝区叩击痛阴性，移动性浊音阴性；肠鸣音正常存在。双下肢无水肿。生理反射存在，病理征未引出。左侧足背部可见一约3cm*3cm红斑。,血常规示：WBC20.6109/LRBC：3.531012/LHGB：93g/LW-LCR0.829C反应蛋白（2011-5-31北京XX医院）42g/L。风湿三项（2011-6-7XX总医院）：ASO296IU/mlRF3000g/dL),orsCD25significantlyaboveage-adjustednormalranges,generallypromptustopursueacompleteHLHdiagnosticevaluation,LiverdiseaseandcoagulopathyMostpatientshavevariableevidenceofhepatitisatpresentation.HLHshouldbeconsideredinthedifferentialdiagnosisofacuteliverfailure,especiallyiflymphocyticinfiltratesarenotedonbiopsy.Autopsyevaluationoftheliverhasshownchronicpersistenthepatitiswithperiportallymphocyticinfiltrationin22of27patientswithHLH.52NeonateswithHLHmaypresentwithhydropsfetalisandliverfailure.53Veno-occlusivediseasemayarisespontaneouslyinpatientswithHLH,andratesofveno-occlusivediseaseashighas25%arereportedafterbonemarrowtransplantation.54Nearly95%ofpatientshavefeaturesofdisseminatedintravascularcoagulationandareathighriskforacutebleeding.49Furthermore,patientswithHLHresultingfromdegranulationdefectsmaymanifestplateletdysfunction.55,BonemarrowfailureAnemiaandthrombocytopeniaoccurin80%ofpatientsatthetimeofpresentationwithHLH.49,51Thecellularityofbonemarrowaspiratesvariesfromnormocelluartohypocellularorhypercellular.Prevalenceofhemophagocytosis(examplesinFigure4)inassociationwithHLHdiagnosisrangesfrom25%-100%,with1-10hemophagocytesper500cellsincasesreportedaspositive.9AlthoughhemophagocytosisinbonemarrowisassociatedwithHLH,themorphologicphenomenonmayalsobeinducedbymorecommonevents,includingbloodtransfusions,infection,autoimmunedisease,andotherformsofbonemarrowfailureorcausesofredbloodcelldestruction.5658DespitethenomenclatureofHLH,diagnosisshouldneverbemadeorexcludedsolelyonthepresenceorabsenceofhemophagocytosis.Infiltrationofbonemarroworliverbyactivatedmacrophages,alongwithglobalclinicalevaluation,maydistinguishHLHfromothercausesofhemophagocytosis.,Hemophagocytosisonbonemarrowaspirateandbiopsy.(A)Twoexamplesofmacrophagesidentifiedonbonemarrowaspiration(Wright-Giemsastain).(B)CD163stainingofbonemarrowbiopsysectionhighlightshemophagocytosis(counterstainedwithhematoxylin).ImagesweretakenonaNikonElipsemicroscope(panelA:100/10;panelB:20/10)withoutoil,withaSpotdigitalcamera.Imagesareunmanipulated.CourtesyofDrJunMo.,SkinmanifestationsPatientsmayhaveavarietyofskinmanifestations,includinggeneralizedmaculopapularerythematousrashes,generalizederythroderma,edema,panniculitis,morbilliformerythema,petechiae,andpurpura.1,59Theincidenceofskinmanifestationsrangesfrom6%-65%inpublishedserieswithhighlypleomorphicpresentations.50,60,61SomepatientsmaypresentwithfeaturessuggestiveofKawasakidisease,includingerythematousrashes,conjunctivitis,redlips,andenlargedcervicallymphnodes.62Rashesmaycorrelatewithlymphocyteinfiltrationonskinbiopsy,andhemophagocytosismayalsobefound.,PulmonarydysfunctionPatientsmaydeveloppulmonarydysfunctionthatleadstourgentadmissiontotheintensivecareunit.Inareviewoftheradiographicabnormalitiesin25patients,17hadacuterespiratoryfailurewithalveolarorinterstitialopacities,withfataloutcomesin88%ofthosecases.WorseningpulmonaryfunctionisanominoussignandshouldsuggestinadequatecontrolofHLHand/orinfection.63,Brain,ophthalmic,andneuromuscularsymptomsMorethanone-thirdofpatientswillpresentwithneurologicsymptoms,includingseizures,meningismus,decreasedlevelofconsciousness,cranialnervepalsy,psychomotorretardation,ataxia,irritability,orhypotonia.64Thecerebrospinalfluid(CSF)isabnormalin50%ofHLHpatientswithfindingsofpleocytosis,elevatedprotein,and/orhemophagocytosis.64MRIfindingsarevariable,includingdiscretelesions,leptomeningealenhancement,orglobaledema,andimagescorrelatewithneurologicsymptoms.65Retinalhemorrhages,swellingoftheopticnerve,andinfiltrationofthechoroidhavebeenreportedininfantswithHLH.6668Diffuseperipheralneuropathywithpainandweaknesssecondarytomyelindestructionbymacrophagesmayalsooccur.69,70,嗜红细胞综合征的治疗：,TreatingHLHWithouttherapy,survivalofpatientswithactivefamilialHLHis2months.60,61ThefirstinternationaltreatmentprotocolforHLHwasorganizedbytheHistiocyteSocietyin1994andledtoreportedsurvivalof55%,withamedianfollow-upof3.1years.71TheHLH-94protocol,asillustratedinFigure5,includedan8-weekinductiontherapywithdexamethasone,etoposide,andintrathecalmethotrexate.Theprincipalgoalofinductiontherapyistosuppressthelife-threateninginflammatoryprocessthatunderliesHLH.Attheendof8weeks,patientsareeitherweanedoffoftherapyortransitionedtocontinuationtherapy,whichisintendedonlyasabridgetotransplantation.,家族性噬血细胞综合征a.化学疗法：常用的化疗药物有细胞毒性药物，如长青花碱或长春新碱与肾上腺皮质激素联用，亦可应用反复的血浆置换，或VP16或VM26与肾上腺皮质激素合用。有的应用VP16、肾上腺皮质激素，鞘内注射氨甲煤呤(MTX)及头颅照射治疗取得良好效果。有的主张在缓解时，应用上述药物小剂量维持治疗。,b.免疫治疗：有人用环胞菌素A治疗家族性HPS取得满意效果，同样，用抗胸腺细胞球蛋白(ATG)亦可诱导缓解。,c.造血干细胞移植：尽管上述化疗可使病情缓解，有的可缓解9年，但仍不能根治家族性HPS。Fisher等(1986)首先报告用骨髓移植治愈家族性HSP患者，在2000年上海举行的国际小儿血液肿瘤学术研讨会上，日本学者Imashukn报告5例由EBV所致的HPS，应用造血干细胞移植，随后用环胞菌素A加VP16，大大改善了本病的预后。,d.治疗方案：国际组织细胞协会1994年提出一个治疗家族性HPS的方案(HLH94):地塞米松每日10mg/m2与VP16每周150mg/m2，连用3周，第4周起减量，第9周起VP16每2周用药1次，并加用环胞菌素A每日56mg/kg口服，共用1年。有神经症状者，前8周每2周鞘内注射MTX1次。如果是家族性HPS，争取做异基因造血干细胞移植。如果为非家族性HPS，则在8周治疗后根据病情停止治疗。,原发性HPS或病因不明未检出明显潜在疾患者除加强支持治疗和并发症的治疗外，目前尚无特效治疗，根本性治疗是同种异体造血干细胞移植。继发性HPS应作病因探索，治疗应以基础病与HPS并重。,继发性噬血细胞综合征,继发性HPS针对病因进行相应治疗。对HPS或高细胞因子血症的治疗对策为：类固醇疗法或大剂量甲基强的松龙冲击；静脉滴注大剂量丙种球蛋白（多用于VAHS）；抑制T细胞活化的特异性抑制剂环孢菌素A或联用G-CSF治疗VAHS，或抗胸腺细胞球蛋白；,直接拮抗细胞因子的抗TNF抗体和IL-1受体拮抗剂；为抑制或减少淋巴因子的供应源可采用化疗。包括CHOP、CHOPE方案或缓慢静滴长春新碱。屡已报道应用依托泊甙（VP16）治疗原因不明的重症HPS、EBV-AHS或LAHS奏效。预后分析表明，对于不易与MH鉴别的HPS患者启用化疗是必需的；骨髓扫荡性（根治性）治疗和异基因骨髓移植（allo-BMT）或外周血干细胞移植治疗FHL或耐化疗的LAHS或EBV-AHS病例，优于常规化疗和免疫抑制治疗。,肿瘤相关性噬血细胞综合征治疗方案决定于疾病的类型，如HPS发生于治疗前的免疫缺陷患者，则治疗主要是抗感染及抗肿瘤；如果HPS发生于化疗后，而肿瘤已缓解则应停止抗肿瘤治疗，同时抗感染，加用肾上腺皮质激素及VP16；对进展迅速的MAHS则应针对细胞因子所致的损害进行治疗，可用前述HLH94方案。,NewtherapeuticapproachesAsanalternativeapproachtoetoposide-basedapproaches,ATG/prednisonehavebeenused.54Althoughasignificantnumberofpatientsfailtorespondadequatelyorcompletelytoetoposide-basedregimens,ATG-basedregimensarecomplicatedbyrelativelyfrequentandearlyrelapse;mediantimetorelapsereportedbyOuachee-Chardinetalwas5.5weeks.54Thus,arationalcombinationoftheseapproachesmayimproveoutcomesbyincreasinginitialresponsesandmaintainingthemuntilHCTcanbeobtained.Currently,amulticenterclinicaltrial,HybridImmunotherapyforHLHisunderwayinNorthAmerica(/ct2/show/NCT01104025).Inthisapproach,ATGandetoposideareincorporatedintooneregimen,buttheetoposidedoseintensityisdecreasedtominimizepotentialmyelosuppression.,AlthoughHLHappearstobeadiseaseofexcessiveimmuneactivation,theidealformofimmunesuppression/anti-inflammatorytherapyremainsunknown.Althoughsomewhatresponsivetocorticosteroidsandclearlyresponsivetoetoposideoranti-T-cellserotherapy(ATGoralemtuzumab),HLHremainsdifficulttotreat.Inthefuture,avarietyofrationallydesignedimmunosuppressiveagentsarelikelytocomeintoclinicalusefortransplantationorautoimmunedisorders.Someoftheseagentsmayalsoprovetobeusefulforthetreatment