Chinese Journal of Tissue Engineering Research ›› 2014, Vol. 18 ›› Issue (27): 4423-4428.doi: 10.3969/j.issn.2095-4344.2014.27.026
Huang Yun-fan, Chen Hong, Wang Xu, Fan Tie-yan
Online:
2014-06-30
Published:
2014-06-30
Contact:
Chen Hong, M.D., Chief physician, Master’s supervisor, Transplantation Institute, General Hospital of Armed Police Forces, Beijing 100039, China
About author:
Huang Yun-fan, Studying for master’s degree, Physician, Transplantation Institute, General Hospital of Armed Police Forces, Beijing 100039, China
CLC Number:
Huang Yun-fan, Chen Hong, Wang Xu, Fan Tie-yan. Cytomegalovirus infection after liver transplantation: its effects on rejection and graft[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(27): 4423-4428.
2.1 肝移植后巨细胞病毒感染的流行病学特点 人类巨细胞病毒属于β疱疹病毒科,是人类疱疹病毒组中最大的一种病毒,细胞感染此病毒后体积会增大,故名巨细胞病毒。巨细胞病毒感染范围较广,人群中血清巨细胞病毒IgG阳性率各地各异,在大多数发达国家,其阳性率大约为 50%,而在发展中国家,成人和大龄儿童的阳性率则高达90%-100%,在中国内陆地区巨细胞病毒IgG阳性率高于发达的沿海地区[10]。血清巨细胞病毒IgG阳性率高的地方,器官移植后巨细胞病毒感染的发生率可能较低,因为群体对巨细胞病毒的免疫力有所增强[11]。在没有使用预防性抗病毒治疗的情况下,肝移植后患者巨细胞病毒的感染率为25%-85%。有报道显示普遍预防治疗与不预防相比能将巨细胞病毒病的发生率降低58%-80%,将巨细胞病毒感染的发生率降低40%左右;而恰当使用口服更昔洛韦、静脉更昔洛韦或缬更昔洛韦进行抢先治疗能将巨细胞病毒病的发生率降低大约70%[12]。 2.2 肝移植后发生巨细胞病毒感染的危险因素 供受者的血清巨细胞病毒状态对肝移植后巨细胞病毒感染的发生有不同程度的影响。血清巨细胞病毒阴性的受者接受血清巨细胞病毒阳性的供肝(巨细胞病毒 D+/R-),其发生巨细胞病毒感染的风险最高,而巨细胞病毒 D-/R-的风险最低,巨细胞病毒 R+的风险则处于两者之间[13]。在普遍预防治疗情况下,认为巨细胞病毒 D+/R-的肝移植患者与移植物的存活、排异反应和巨细胞病毒感染或巨细胞病毒病的迟发有关联[14]。而ABO血型不相容的肝移植也被证实为住院期间巨细胞病毒感染的危险因素[15]。其他与肝移植后巨细胞病毒发生有关的因素还包括较低的肌酐清除率、女性患者、移植物排斥反应、使用的免疫抑制剂方案[13]。 近期有研究明确提出供受者的MBL-2和FCN-2基因多态性是肝移植后巨细胞病毒感染的独立危险因素[16]。人类甘露糖结合凝集素基因包括MBL-1和MBL-2两个基因,MBL-1是假基因,MBL-2基因才具有编码蛋白质的功能,而天然免疫分子甘露糖结合凝集素在血清中的表达水平与MBL-2基因多态性密切相关,MBL-2基因发生变异会导致甘露糖结合凝集素水平下降,正如有研究显示术前甘露糖结合凝集素水平(< 500 μg/L)是肾移植后巨细胞病毒感染的独立危险因素[17]。 2.3 肝移植后巨细胞病毒感染的临床表现及诊断 肝移植后的巨细胞病毒感染按其临床表现可以分为两种情况:巨细胞病毒感染(巨细胞病毒血症)和巨细胞病毒病(巨细胞病毒综合征和巨细胞病毒器官侵袭病变)。当病毒学检查仅血清巨细胞病毒IgG阳性,称为静止性巨细胞病毒感染;在患者血清中巨细胞病毒IgM阳性和(或)巨细胞病毒pp65阳性时称活动性巨细胞病毒感染。巨细胞病毒感染无临床症状,而巨细胞病毒病有临床症状,即出现巨细胞病毒综合征(发热、骨髓抑制、皮疹)或巨细胞病毒侵入肺、肝脏、胃肠道等引起的相应组织病变。如临床上较常见的巨细胞病毒性肺炎,发热、呼吸困难、咳嗽和低氧血症为其主要的临床表现,肺部CT以间质性改变为主,表现为双肺典型的磨玻璃样、云雾状炎症渗出;巨细胞病毒性肝炎可能只有轻微的肝功能异常;而其他病变部位的临床表现还可能出现全血细胞减少、腹泻、视网膜炎等。 由于肝移植后巨细胞病毒感染对患者有严重影响,应尽早发现并诊治,因此除了临床表现外,还需要快速且特异的诊断方法。长期以来,巨细胞病毒IgM抗体阳性或巨细胞病毒IgG抗体滴度上升4倍以上时提示有急性感染,虽然在巨细胞病毒感染的诊断上有一定的作用,但对于免疫功能不全的患者其敏感性不高。巨细胞病毒pp65抗原检测作为诊断巨细胞病毒感染的金标准,有报道显示与巨细胞病毒pp65相比,运用PCR技术快速进行巨细胞病毒DNA定量分析在临床应用上具有更高的敏感性和特异性,但费用较昂贵[18]。Ji等[19]研究显示实时荧光定量逆转录聚合酶链反应(RT-PCR)在肝移植后巨细胞病毒感染的诊断上是一个有效的工具,单独行巨细胞病毒pp65抗原检测具有较高的假阳性率和不准确性,尤其是在阳性细胞较低的情况下,这会延误治疗。先用pp65抗原检测进行筛查,再用实时RT-PCR技术进一步诊断,将两者相结合可能是诊断巨细胞病毒感染的一个最佳、且成本较低方案。但是,由于不同PCR试验的应用,对最理想的样本材料仍有争议。Chen等[20]为了探索肝移植后对巨细胞病毒DNA进行监测的最佳血液成分,对全血、血清、血浆3种样本材料进行了研究,与血清或血浆相比,全血样本材料能更早发现阳性结果、有更高的敏感性以及产生更大的病毒载量,因此被认为是肝移植后监测巨细胞病毒DNA的优质材料。另外,因巨细胞病毒病感染的部位不同,诊断方法也有所差异,如巨细胞病毒性肝炎可采用肝穿进一步明确诊断,其组织学特征包括中性粒细胞积聚的微脓肿或肝小叶内弥漫性小结节,如再加上在炎症部位附近发现含有核内或胞浆包涵体的巨细胞,则高度提示巨细胞病毒感染,但特异性不高,与其他病毒性肝炎难以区分。而肺部CT对巨细胞病毒性肺炎是一个好的选择。 2.4 肝移植后巨细胞病毒感染对机体的影响 肝移植后巨细胞病毒感染对机体的影响分为直接和间接影响。直接影响包括巨细胞病毒综合征、器官侵袭病变(如肺炎、肝炎、胃肠道疾病、中枢神经系统病变、视网膜炎等)及移植物失功。巨细胞病毒感染对患者的间接影响也是多方面的,首先,它能增加丙肝复发的风险。Bosch等[21]在一个单中心大样本(347例)的回顾性分析中得出无论是巨细胞病毒感染或巨细胞病毒病都与加速肝移植后丙肝复发有关,在此之前虽也有报道巨细胞病毒感染与丙肝复发有关,但均基于一些小样本的研究。由于巨细胞病毒是潜在的自身抗原调节因子,因此它可以增加急性和慢性排斥反应的发生率。有报道显示器官移植后出现巨细胞病毒病的患者有更高的急排发生率,能降低患者和移植物的存活时间,从而增加死亡率[22]。但近期也有数据显示巨细胞病毒感染或巨细胞病毒病不会促进实体器官移植后长期不良事件的发生[23]。除此之外,巨细胞病毒感染还会增加机会性或其他感染的发生率。因为巨细胞病毒对机体的免疫有损伤作用,特别是细胞免疫。当巨细胞病毒感染到外周血单核细胞和淋巴细胞后,T细胞对植物凝集素的增殖反应下降,白细胞介素1和白细胞介素2的生成以及T细胞对白细胞介素2的应答会受损,从而影响T细胞的活化和增殖,细胞免疫受到破坏,从而导致免疫抑制。除此之外,巨细胞病毒感染还会严重影响机体自然杀伤细胞的杀伤能力[24]。巨细胞病毒感染已被认为是引起细菌和真菌双重感染的一个独立危险因素[25]。另外,巨细胞病毒感染会加速动脉硬化,且与β-疱疹病毒之间存在相互作用。 2.5 肝移植后巨细胞病毒病的治疗 肝移植后用于治疗巨细胞病毒病的抗病毒药物有更昔洛韦、缬更昔洛韦、阿昔洛韦、西多福韦和膦甲酸钠等。目前,更昔洛韦已成为肝移植后治疗巨细胞病毒病的首选药物。更昔洛韦治疗的标准剂量为5 mg/kg,每12 h 1次。由于更昔洛韦主要经肾脏代谢,对于肾功能不全的患者应酌情减量。更昔洛韦也可以口服给药,但口服用药吸收有限,由此限制了其在治疗巨细胞病毒病上的应用,实际上,口服的更昔洛韦不适用于治疗巨细胞病毒病。近年来,作为更昔洛韦的缬氨酰前体,缬更昔洛韦开始上市并被应用于临床,与更昔洛韦相比,该药口服吸收好,血药浓度几乎与静脉更昔洛韦的水平相当,有研究显示口服的缬更昔洛韦与静脉更昔洛韦在肝移植后巨细胞病毒感染的抢先治疗上同样安全有效[26]。由于西多福韦、膦甲酸钠以及阿昔洛韦在不良反应或疗效方面的限制,目前临床已很少应用。除了抗病毒药物外,巨细胞病毒免疫球蛋白也被用于治疗巨细胞病毒感染,但有关其疗效的研究报道不一。由于免疫球蛋白费用昂贵,目前又有高效而廉价的抗病毒药物,均限制了巨细胞病毒免疫球蛋白在临床的广泛应用。近期,Fisher等[27]研究显示肝移植后巨细胞病毒免疫球蛋白与抗病毒药同时使用时会增加急性排斥反应的风险,但能够降低移植物失功和死亡的风险。因为巨细胞病毒感染会引起强烈的炎症反应,而这些炎症介质是否与临床结果有某种相关性,Rollag等[28]就对其做了相关研究,结果表明在实体器官移植后对发生巨细胞病毒病的患者进行抗病毒治疗时,其治疗前CXCL16、PTX3、血管性血友病因子的血浆水平与临床治疗失败有独立相关性。从中可以得知巨细胞病毒感染与炎症之间的关系对抗病毒治疗的结果可能有一定影响。 2.6 肝移植后巨细胞病毒感染的预防 巨细胞病毒感染作为肝移植后一个较为普遍的并发症,一旦发生,有众多不良影响,因此预防显得尤为重要。目前广为临床所接受的预防肝移植后巨细胞病毒感染方案有两种:普遍预防治疗:对全部或某些患者在肝移植后不久即给予抗病毒治疗,并在预定终点停止治疗。常用方案包括:静脉注射更昔洛韦2周方案;持续口服更昔洛韦或缬更昔洛韦3个月方案;静脉注射更昔洛韦2周后改持续口服更昔洛韦或缬更昔洛韦3个月方案。优先或抢先治疗:在病毒学检测提示存在巨细胞病毒感染后开始行抗病毒治疗,此时尚未出现临床症状,防止它进一步向巨细胞病毒病发展。 总体来讲两种方案均能有效控制巨细胞病毒感染的发生[13, 29],但各自有优缺点,尚存在诸多不同观点。抗病毒治疗本身就存在一些不良反应,如骨髓抑制及肝肾功能损害等。普遍预防治疗时间较长,经济负担较重,且存在迟发现象;其优点是预防人群的范围较广,且对巨细胞病毒感染及巨细胞病毒病都有较好的预防作用。而抢先治疗则更具有针对性,可减少部分患者的经济负担,但总体预防人群的范围较窄,只预防已出现巨细胞病毒感染的患者向巨细胞病毒病发展。前几年的研究显示在美国和加拿大的大部分肝移植中心均较偏向于普遍预防治疗方案[30]。而目前对供受者血清巨细胞病毒状态这个因素的预防方案的研究较多。Katsolis等[31]指出应对所有高危肝移植患者(巨细胞病毒D+/R-)均应有计划的干预巨细胞病毒感染,直至我们明确巨细胞病毒感染引起并发症的更多预测因子。有报道对高危肝移植患者在预防巨细胞病毒病的发生上进行了研究,得出普遍预防治疗比抢先治疗更有效[32]。Kim等[33]的研究结果显示对巨细胞病毒D+/R+的肝移植患者在预防巨细胞病毒病的发生上,普遍预防治疗和抢先治疗有同等的功效。而Lautenschlager等[34]对巨细胞病毒R+的肝移植患者进行了一个前瞻长期的随访研究,得出大部分血清巨细胞病毒R+的患者不会出现巨细胞病毒的再活化,如果出现了巨细胞病毒感染,大部分都是无症状的、短暂的、巨细胞病毒DNA水平较低的情况,有高病毒载量和临床症状的患者都能被成功救治并且较少复发,对于这类患者采用抢先治疗比普遍预防治疗更加适用。Davoudi等[35]也得出了相同的结果。肝移植后运用普遍预防治疗可引起巨细胞病毒感染的迟发现象[36],有报道就对实体器官移植后,使用普遍预防治疗后巨细胞病毒感染的发生率进行了研究,在肝移植患者中巨细胞病毒D+/R-组与其他组(巨细胞病毒D+/R+、巨细胞病毒D-/R+、巨细胞病毒D-/R-)相比,其移植后巨细胞病毒病的迟发率更高,但该组的巨细胞病毒感染并不增加死亡率;在肾移植患者中巨细胞病毒D+/R+组有症状的巨细胞病毒感染所占比例较高,而该组的巨细胞病毒感染与高死亡率有关[37]。但无论供受者血清状态如何,肝移植后大约有25%的患者发生巨细胞病毒感染,且这个比例不足以通过普遍预防治疗的方法减少[13],而且无论是采用普遍预防治疗还是抢先治疗,都与巨细胞病毒引起的严重负面临床结果无关联[38]。而何为肝移植后最好预防巨细胞病毒感染的方法,目前仍存在争论[39]。 有实验和临床数据显示mTOR抑制剂(如西罗莫司和依维莫司)可能具有抗巨细胞病毒的作用,国外一荟萃分析显示mTOR抑制剂单独或与钙调神经蛋白抑制剂类药物同时使用时能降低实体器官移植后巨细胞病毒的发生率,在运用mTOR抑制剂的情况下,巨细胞病毒的预防可能不是必须的[40]。"
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