心肺移植患者巨细胞病毒耐更昔洛韦基因突变研究

目的　建立并应用人巨细胞病毒 (HCMV)行列探针检测 (LiPA)技术 ,快速检测心肺移植患者HCMV耐更昔洛韦 (GCV)基因突变。方法　以HCMV UL97基因为靶序列 ,设计 13条特异性寡核苷酸探针 ,用Nested PCR扩增目的基因 ,LiPA技术检测与耐药有关的碱基突变。并对Nested PCR产物平行做直接序列测定 ,与LiPA结果比较。结果　 16例心肺移植患者 ,LiPA技术检测发现 4例患者存在HCMV UL97基因突变 ,突变分别发生在编码子 5 2 0 ,5 95及 6 0 3,与直接序列测定比较 ,两者完全吻合。结论　长期应用GCV预防及治疗HCMV感染可以诱导病毒耐药 ,LiPA技术可作为检测HCMV基因突变的一种有效手段。     

更昔洛韦治疗巨细胞病毒性肝炎12例观察

婴儿巨细胞病毒(Cytomegatovirus，CMV)性肝炎，为新生儿CMV性肝炎的延续，亦可为生后获得性感染所致，起病缓慢而隐匿。临床上以阻塞性黄疸，肝脾肿大，肝功能受损为特征。近2年来我们应用更昔洛韦治疗CMV性肝炎12例，疗效满意。现报告如下。     

缬更昔洛韦预防肾移植患者术后巨细胞病毒感染的体会

巨细胞病毒（cyto—megalovirus，CMV）感染和CMV病是肾移植术后最严重的并发症和致死的重要病因。肾移植近期因CMV感染导致的死亡率占2％。肾移植后6个月内是CMV感染和发生CMV病的高发期，也是免疫抑制剂药量最大的时期，如防治不当，会严重影响肾移植的效果。     

更昔洛韦治疗婴幼儿巨细胞病毒肝炎疗效观察

巨细胞病毒 ( CMV)感染在我国相当普遍 ,较大儿童和成人感染 CMV后无症状 ,而婴幼儿则常表现为肝炎 ,严重者易出现肝功能衰竭或继发感染 ,从而危及生命。目前 CMV肝炎无特效治疗方法 ,2 0 0 1年 1月至 2 0 0 2年 1 2月 ,我院采用更昔洛韦 ( GCV)治疗婴幼儿 CMV肝炎 ,取得较好疗效。现报告如下。1　资料与方法1 .1　临床资料　本文 2 9例患儿 ,均符合 CMV肝炎诊断标准[1] 。其中男 1 8例 ,女 1 1例 ;年龄 34天至 5个月 ,平均 2 .8个月。临床表现为肝大 2 4例 ,脾大 1 8例 ,黄疸 2 9例 ,出现腹水 2例 ;肝功能检查示 GPT( 99.7± 42 .…     

长疗程口服更昔洛韦预防肾移植术后巨细胞病毒病

目的:探讨长疗程口服更昔洛韦预防肾移植术后巨细胞病毒(CMV)病的有效性及安全性。方法:2004年1月至2007年1月在本院进行首次肾移植的57例患者,分为预防组和对照组。预防组27例,术后即予更昔洛韦口服,每次1g,3次/d,维持用药3个月;对照组30例,不服用任何抗病毒药物。结果:长疗程预防性口服更昔洛韦能降低CMV病发病率(14.8%比20.0%),但未达到统计学差异(P>0.05);能明显推迟CMV病发病时间[(77.3±11.1)d比(63.2±14.1)d,P<0.05];降低CMV病发病时的严重程度,缩短病程[(11.5±2.2)d比(13.0±1.0)d,P0.05);预防组中2例发生不良反应。结论:长疗程口服更昔洛韦对CMV病的发病率无显著影响,但可降低CMV病的病死率,缩短病程。口服更昔洛韦的不良反应少。     

更昔洛韦治疗婴儿巨细胞病毒肝炎26例疗效观察

20 0 0年 2月至 2 0 0 2年 7月 ,我院采用更昔洛韦治疗婴儿巨细胞病毒 ( CMV)肝炎 2 6例 ,总结如下。1　资料与方法1 .1　临床资料　 46例 CMV肝炎患儿中 ,男 2 7例 ,女1 9例 ;年龄 32天至 6个月 ;病程 7天至 5个月 ,平均 2个月。患儿均有黄疸 ,肝脏肿大 46例 ,脾脏肿大 2 5例 ,出生低体重 3例 ,早产儿 2例 ,小头畸形 2例 ,合并肺炎3例 ,皮肤瘀点、瘀斑 6例 ,脑积水 3例。实验室检查 :患儿血清总胆红素均升高 ,并肝功能异常 ;晨尿CMV- DNA( + ) ,血清 CMV- Ig M( + ) ;乙肝五项及丙肝抗体均阴性 ,并排除代谢性肝病、药物和中毒性肝炎…     

更昔洛韦和膦甲酸钠预防异基因造血干细胞移植后巨细胞病毒感染效果比较的单中心、前瞻性随机对照研究

目的:比较膦甲酸钠和更昔洛韦预防用药对异基因造血干细胞移植(allo-HSCT)后巨细胞病毒(CMV)感染的疗效及安全性,为有效预防allo-HSCT后CMV感染提供临床参考。方法:前瞻性随机选取行allo-HSCT的69例患者,随机分为膦甲酸钠组60 mg/(kg·d)和更昔洛韦组5 mg/(kg·d),对2组患者用药期间和移植+100 d CMV感染及毒副作用进行临床观察,比较2种药物在allo-HSCT后CMV感染预防中的效果和安全性。结果:预防用药期间、移植+100 d CMV感染和CMV病发生率,更昔洛韦组分别是2.9%、20.6%、0,而膦甲酸钠组分别为11.4%、31.4%、11.4%;2组上述指标差异均无统计学意义(P>0.05);但膦甲酸钠预防组CMV感染出现时间明显先于更昔洛韦预防组(P=0.015);毒副作用方面:2组用药期间,Ⅲ度粒细胞减少的发生,更昔洛韦组明显高于膦甲酸钠组(P=0.016);Ⅳ度粒细胞减少在2组间差异无统计学意义;2组在Ⅰ、Ⅱ度血小板减少的发生率上差异也无统计学意义;2组肾功能损害发生率相似,但电解质紊乱发生率在膦甲酸钠预防组较更昔洛韦...     

异基因造血干细胞移植后巨细胞病毒感染的预先治疗

目的:探讨预防治疗及预先治疗对异基因造血干细胞移植后CMV感染的干预作用.方法:225例异基因造血干细胞移植患者中160例接受预先治疗,65例接受预防治疗,用logistic回归模型分析影响CMV感染的危险因素.结果:预先治疗组与预防治疗组比较,CMVpp65抗原血症、CMV病和CMV病死亡率分别为28.1%(35.3%,P>0.05),1.9%(12.3%,P<0.05)和0.6%(10.7%,P<0.01).单倍体相合移植组出现CM-Vpp65血症33.0%(40.0%,P>0.05)、CMV病发生率1.9%(12.0%,P<0.05)、死亡率0.0%(10.0%,P<0.05),均低于相合移植.单倍体相合移植组中CMVpp65阳性发生的主要危险因素为重症GVHD、移植前给予抗CMV治疗以及是否混合其他严重感染.结论:异基因移植后预先治疗优于预防治疗,可以明显减低CMV病的发生和死亡.     

更昔洛韦联合中药方剂治疗新生儿巨细胞病毒肝炎效果观察

目的 探讨更昔洛韦联合中药方剂治疗新生儿巨细胞病毒（CMV）肝炎的临床疗效。 方法 2015年4月~2016年8月在海南省妇幼保健院接受治疗的CMV肝炎新生儿62例,随机将患儿分为对照组31例和联合组31例。给予对照组更昔洛韦抗病毒治疗,联合组在对照组治疗的基础上给予自拟中药方剂口服,连续治疗4~6 w。 结果 治疗前,两组患儿血清TBIL、ALT、GGT、TBA水平无显著性差异（P>0.05）,在连续治疗4~6 w后,两组患儿血清肝功能指标均恢复正常,但联合组患儿黄疸消退时间、肝脏回缩时间和脾脏回缩时间分别为（13.7±5.5） d、（18.1±6.3） d和（21.4±8.3） d,均显著短于对照组【（18.9±7.4）d、（22.6±8.8）d和（25.7±9.7）d,P<0.05】;在治疗期间,对照组有2例患儿外周血白细胞分别下降至2.8×109/L和3.1×109/L,2例患儿血小板分别下降到64×109/L和69×109/L,联合组也有2例患儿白细胞或血小板计数下降,但均为一过性,自动恢复。 结论 更昔洛韦联合中药方剂治疗新生儿CMV肝炎能缩短病程,加快病情恢复。     

更昔洛韦联合茵栀黄治疗婴儿巨细胞病毒性肝炎初步研究

目的探讨更昔洛韦联合茵栀黄口服液治疗婴儿巨细胞病毒性肝炎的临床效果。方法2015年1月~2016年12月我院门诊和病房收治的的巨细胞病毒性肝炎患儿76例,采用随机数字表法将其随机分为对照组38例和观察组38例。给予对照组患儿更昔洛韦静脉滴注,观察组患儿在对照组治疗的基础上给予茵栀黄口服液口服。采用ELISA法检测血清TNF-α和IFN-γ,采用荧光定量PCR法检测血清CMV DNA载量。结果在治疗2 w末,观察组患儿血清ALT、AST、TBIL、TBA水平分别为（24.1±9.1）U/L、（24.6±10.3）U/L、（3.7±1.4）μmol/L、（24.3±8.6）μmol/L,均显著低于对照组的（58.3±18.6）U/L、（58.3±26.9）U/L、（28.6±13.7）μmol/L、（38.5±15.4）μmol/L（P<0.05）;血清TNF-α水平为（30.4±7.1）pg/ml,显著低于对照组的（35.3±7.5）pg/ml（P<0.05）;观察组和对照组患儿血清IFN-γ水平分别为（40.7±8.3）pg/ml和（39.3±7.9）pg/ml,差异无统计学意义（P>0.05）;观察组患儿血清CMV DNA转阴率为100.0%,对照组为97.4%,两组差异无统计学意义（P>0.05）。结论更昔洛韦联合茵栀黄口服液治疗婴儿巨细胞病毒性肝炎,在保护肝功能、降黄、利胆、病毒转阴和调节机体免疫功能方面效果显著。     

Ganciclovir预防异基因造血干细胞移植后巨细胞病毒感染

目的 :评价Ganciclovir在异基因造血干细胞移植 (allo HSCT)后预防巨细胞病毒 (CMV)感染的效果。方法 :观察allo HSCT患者 46例 ,全部病例均系移植前受者和 (或 )供者的CMV IgG阳性 ,分为预防组 2 4例 ,对照组 2 2例。allo HSCT后当患者血中性粒细胞 >1.0× 10 9/L时 ,预防组开始用GCV 10mg·kg-1·d-1,分两次静滴 ,连续 5d ;然后改为 5mg·kg-1·d-1,每周用 5d ,直至 +10 0d。对照组未预防性使用GCV。结果 :在 +10 0d内 ,预防组和对照组的CMV感染率分别为 8% (2 / 2 4)、32 % (7/ 2 2 ) ,P <0 .0 5 ;CMV病发病率分别为 0 %、18% (4 / 2 2 ) ,P <0 .0 5。两组患者在 +10 0d和 +180d内的死亡率分别为 4% (1/ 2 4)和 5 % (1/ 2 2 ) ,P >0 .0 5 ;12 .5 % (3/ 2 4)和 9% (2 / 2 2 ) ,P >0 .0 5。预防组的死因分别为并发细菌和真菌感染、CMV间质性肺炎或原发病复发 ;对照组的死因均是CMV间质性肺炎。结论 :allo HSCT后预防性使用GCV能明显抑制CMV感染 ,减少CMV病发病率。GCV的主要毒副作用是导致中性粒细胞减少 ,使患者继发感染甚至死亡的机率增加。GCV预防性使用的最佳剂量、用药方案及持续时间均有待进一步探讨     

Endoscopic diagnosis of cytomegalovirus gastritis after allogeneic hematopoietic stem cell transplantation

AIM:To clarify the endoscopic and clinical findings of cytomegalovirus(CMV) gastritis after allogeneic hematopoietic stem cell transplantation(allo-SCT).METHODS:Between 1999 and 2005,523 patients underwent allo-SCT at our hospital,and 115 of these patients with gastrointestinal symptoms underwent esophagogastroduodenoscopy.RESULTS:CMV gastritis was diagnosed pathologically in seven patients(1.3%) with the other 108 patients serving as controls.Six of the seven patients developed positive CMV antigenemia,and...     

Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation

Late cytomegalovirus (CMV) disease beyond day 100 after hematopoietic stem cell transplantation (HSCT) has become an increasing problem after the introduction of preemptive ganciclovir (GCV) administration. To clarify the risk factors and outcome for late CMV reactivation and disease, we retrospectively analyzed the records of 101 Japanese adult patients who underwent allogeneic HSCT between 1998 and 2005 at our hospital. Fifty-one developed late positive CMV antigenemia, with a cumulative incidence of 53%. Recipient CMV seropositivity, the use of alemtuzumab, chronic GVHD, and high-dose steroids were significantly associated with late positive antigenemia. Eight patients developed late CMV disease, with a cumulative incidence of 8%, including retinitis and gastrointestinal disease. None progressed to a fatal disease. The use of alemtuzumab was identified as an independent significant risk factor for late CMV disease, although it was not associated with increased non-relapse mortality. Among the 51 patients with late positive antigenemia, 28 had consistently less than three positive cells, 25 of whom showed negative conversion without antiviral agents. In conclusion, late CMV antigenemia appeared to develop frequently, especially in patients with profound immune suppression; however, a fatal outcome could be prevented by optimal preemptive therapy. Low-level antigenemia may not require antiviral treatments.     

抢先治疗异基因造血干细胞移植后巨细胞病毒感染的临床分析

目的 回顾性分析抢先治疗异基因造血干细胞移植(allo-HSCT)后巨细胞病毒(CMV)感染的临床意义.方法 allo-HSCT治疗的患者103例,采用荧光定量PCR法监测CMV-DNA,并根据其结果抢先治疗CMV相关疾病,分析抢先治疗对于阻止CMV血症发展为CMV相关疾病的意义.结果 103例患者中检测出63例次(51例)CMV-DNA阳性,CMV血症发生率为49.5%,经抢先治疗19例发生CMV相关疾病,发生率为18.4%.60例次CMV血症经更昔洛韦和(或)膦甲酸治疗转阴,1例不可评价疗效,治疗的总有效率为96.8%(60/62).CMV相关疾病的治疗总有效率为89.5%(17/19),2例患者因CMV相关肺炎伴急性GVHD而死亡,CMV相关疾病的直接死亡率为1.9%(2/103).结论 在不进行预防性治疗的前提下,CMV血症和CMV相关疾病发生率未见升高.抢先治疗能有效阻止大部分CMV血症患者发病,并能有效控制CMV相关疾病的进展.     

巨细胞病毒特异性细胞毒性T淋巴细胞治疗造血干细胞移植后难治复发性巨细胞病毒感染的临床分析

目的 探讨体外扩增的巨细胞病毒(CMV)特异性细胞毒性T淋巴细胞(CMV-CTL)在难治复发性巨细胞病毒感染患者中的疗效及安全性.方法 给予28例难治复发性CMV感染患者输注CMV-CTL,其中19例患者CMV-CTL来自造血干细胞移植原供者,9例来自第三方供者.第1疗程输注1～2次,观察疗效和副作用;第1疗程完全缓解(CR)后复发的患者给予第2疗程治疗,输注1～2次.结果 21例CMV血症患者和7例CMV病患者接受CMV-CTL治疗,首次输注CTL中位治疗时间为移植后76(39 ～321)d,CTL输注中位细胞数为1.0(0.5～10.0)×10 7.第1疗程后,21例CMV血症患者和4例CMV病患者获得CR,CMV血症CR率为100％,CMV病CR率为4/7;获得CR的中位时间分别为首次CTL输注后9(3～23)d和7(4～18)d.6例CMV血症患者和1例CMV病患者CR后复发而给予第2疗程治疗,其中4例CMV血症患者和1例CMV病患者获得CR.5例次患者输注后出现移植物抗宿主病,均为轻中度皮肤受累.随访中6例死于CMV感染,2例死于其他移植后并发症.结论 初步结果显示,体外扩增的CMV-CTL输注治疗难治复发性CMV感染安全有效,但输注方案有待进一步完善.     

Oral valganciclovir as preemptive therapy for cytomegalovirus infection post allogeneic stem cell transplantation

Antiviral compounds including ganciclovir, foscarnet, and cidofovir are routinely used in the treatment of cytomegalovirus (CMV) infection and disease; however, these agents have a poor oral bioavailability and have the inconvenience and expense of intravenous administration. AIM OF THE STUDY: To evaluate the safety and efficacy of oral valganciclovir (VGCV) for preemptive treatment of CMV reactivation in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: We treated 15 patients receiving allogeneic HSCT from related (n=9) or unrelated (n=6) donors. In all patients, either the donor, host, or both were CMV Ig G positive pretransplant. Indication for therapy was preemptive treatment of CMV infection defined as one or two consecutive positive tests of pp65 antigenemia assay or CMV-polymerase chain reaction (PCR). VGCV was administered orally in a dosage of 900 mg b.i.d. for 2 weeks, followed by 450 mg b.i.d. for 2 additional weeks. RESULTS: Patients developed a positive CMV-PCR after a median of 52 days (range 37-427) post HSCT and a positive pp65 antigenemia after a median time of 74 days (range 37-427) post HSCT. Preemptive treatment with VGCV was started a median time of 56 days (range 37-429) after transplant. In all, 11 patients (73%) completed the 28 days of therapy with VGCV. All patients showed a complete clearance of the virus. The median time to achieve a negative CMV-PCR was 6 days (range 4-18). A relapse of CMV infection after VGCV preemptive therapy occurred in 6 patients (40%). No patient developed early or late CMV disease. Six patients (40%) presented hematological toxicity including neutropenia and/or thrombocytopenia that required drug discontinuation in 4 cases. CONCLUSION: VGCV administered as preemptive therapy for CMV infection in patients receiving an allogeneic HSCT showed promise for treating this frequent complication. Prospective randomized studies in this setting are mandatory to yield more definitive results.     

Oral valganciclovir as preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients

Between March 2007 and January 2008, the safety and efficacy of oral valganciclovir (VGC) preemptive therapy for cytomegalovirus (CMV) infection was evaluated in ten consecutive patients who received allogeneic hematopoietic stem cell transplantation (HSCT). Patients were screened once or twice per week after engraftment using CMV pp65 antigenemia assay. When more than 2 CMV antigen-positive cells per 50,000 leukocytes were detected, preemptive therapy with oral VGC was initiated at a dose of 900 mg twice daily for 3 weeks. Nine patients (90%) completed the 3-week VGC treatment except for one patient who developed febrile neutropenia. There was no other significant toxicity. CMV antigen-positive cells were rapidly decreased in all nine patients and became undetectable by the end of the VGC treatment. None of the patients developed CMV disease. CMV infection relapsed in four of the ten patients (40%) after the VGC treatment. These observations suggest that preemptive therapy with VGC is effective for preventing CMV disease in allogeneic HSCT patients. Further studies with a large number of patients will be necessary to determine the optimal initial- and maintenance-dose of VGC.     

Risk for cytomegalovirus infection following reduced intensity allogeneic stem cell transplantation

Preliminary data suggest a faster immune recovery following non-myeloablative stem cell transplantation because of the persistence of recipient T cells, but the real impact on post-transplant infectious complications remains unknown. We retrospectively analysed the incidence of cytomegalovirus (CMV) infection in twenty patients following reduced intensity conditioning with busulfan/fludarabine±thiotepa and post-transplant immunosuppression with cyclosporine A/mycophenolate mofetil. Results were compared with 20 patients receiving myeloablative transplants during the same time period and who were matched for CMV risk group and for donor origin. The cumulative incidence of CMV infection following reduced intensity vs. myeloablative transplants was 60.4% vs. 40.0%, respectively (p value 0.1, log rank test). The risk for CMV infection in both cohorts was increased after in vivo T cell depletion with antithymocyte globulin (75% and 60%, respectively). Acute GVHD preceded the diagnosis of CMV infection by a median of 25 (range, 9–61) days following reduced intensity transplants and a median of 14 (range, 10–34) days in myeloablative transplants. Recurrent CMV infections were observed only in patients receiving reduced intensity transplants. Using multivariate analysis only reduced intensity transplantation and in vivo T cell depletion had a significant impact on the risk of CMV infection. In our series the incidence for CMV infection following reduced intensity transplants seems to be increased as compared with risk-matched myeloablative transplants. When adding anti-T cell antibodies to the conditioning regimen, the risk for CMV infection increases by up to 75%. Thorough studies of the risk of post-transplant viral infection are necessary to optimize surveillance as well as pre-emptive and/or prophylactic treatment strategies in the non-myeloablative transplantation setting.