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巨细胞病毒感染 Updated May, 2008
Stephen A. Spector, M.D. Professor Department of Pediatrics Chief, Division of Infectious Disease Member, Center for AIDS Research Member, Moores UCSD Cancer Center University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093-0672 Tel: 858/534-7170; Fax: 858/534-7411 Email: saspector@ucsd.edu
译者：朱岩 总住院医师 北京协和医院 内科 Email：zydream@gmail.com
GENERAL DESCRIPTION 概述 Virology Guided Medline Search 病毒学 Human cytomegalovirus (CMV, HCMV, HHV-5) is a ubiquitous beta herpesvirus that only infects humans and human cells. As with all herpes viruses, CMV is a large, double-stranded DNA virus that contains 162 capsomeres, a tegument between the capsid and envelope, and an envelope containing lipids and glycoproteins that are sensitive to lipid solvents and detergents (155). Once an individual is infected with CMV, the virus establishes latency and may reactivate in persons with normal immune systems and commonly during immunosuppression. In normal immune competent individuals, reactivation of CMV results in local reactivation in urine, saliva, the cervix in women and in semen of men. However, CMV reactivation in the immunocompromised host often results in viremia, and can cause severe and life-threatening infections in persons with deficient cell mediated immunity. The virus commonly crosses the human placenta and is the most common congenital infection in developed countries. 人类巨细胞病毒（Human cytomegalovirus ，CMV, HCMV, HHV-5）属于疱疹病毒亚科，分布广泛，仅能感染人或人类细胞。CMV与其他疱疹病毒相似，是双链DNA病毒，包括162个壳粒（capsomer），包膜与核衣壳之间有无明显构型的被膜(tegument)，包膜含有脂质和糖蛋白，在脂溶剂和去污剂中不稳定（155）。人类感染CMV后，病毒即潜伏于体内，当机体处于免疫抑制状态时病毒感染会再激活。在免疫力正常个体，感染再激活多为局灶性，如尿液、唾液、宫颈（女性）或精液中（男性）。然而在免疫缺陷患者中病毒再激活常表现为病毒血症，尤其在细胞免疫缺陷的患者可引起严重甚至危及生命的感染。CMV病毒可通过胎盘引起胎儿感染，在发达国家中CMV感染是最常见的先天性感染。 Epidemiology Guided Medline Search 流行病学 Human CMV is transmitted from human to human; there is no animal reservoir. The virus has a worldwide distribution and infects all ethnic and socioeconomic groups. CMV is the most common cause of congenital infection found in from 0.4% to 2.5% of infants at birth. After the newborn period, person-to-person transmission occurs most commonly through salivary or sexual contact. Contact with urine can also result in transmission. Mother-to-infant transmission can occur in utero resulting in congenital infection, intrapartum as the infant passes through an infected cervix or through breast milk. From 20% to 40% of healthy women shed CMV into their breast milk and results in infection of 30 to 70% of nursing infants. In the healthy, full-term infant acquisition of CMV via this route rarely results in complications, and the potential of transmitting CMV to infants through human milk is outweighed by the benefits of breastfeeding. Thus, women should be encouraged to nurse their infants without regard to their CMV serostatus. The acquisition of CMV by premature infants may result in symptomatic infection with CMV including fever, pneumonia, gastrointestinal disease and hepatitis (190). In these situations when the use of breast milk is desired, the milk should be expressed and freeze-thawed or heated to decrease the potential infectivity of the milk. CMV感染在人与人之间传播，人是CMV的唯一宿主，它不宿于其他的动物。该病毒为世界性分布，其感染普遍存在于各种族及不同社会经济地位群体。CMV感染是最常见的先天性感染，发生率为0.4%-2.5%。新生儿期后，唾液或性接触为最常见的传播方式。接触带有病毒的尿液也可以引起感染。母婴传播有多种途径，可以是宫内的先天性感染，也可以是产时经过感染的宫颈或母乳喂养时感染病毒。被CMV感染的健康母亲的乳汁有20%-40%中含有CMV，哺乳后，30%-70%的婴儿会受到感染。但健康的足月儿经过这种途径引起的CMV感染很少有器官损害，母乳喂养的益处远远大于潜在CMV感染的危害。因此，即使母亲有CMV感染，也应鼓励母乳喂养。早产儿接触CMV后可能引起有症状性的感染，表现为发热、肺炎、胃肠炎和肝炎（190）。因此，早产儿若需CMV阳性母乳的喂养时，应对母乳进行冷冻-解冻或加热处理降低感染的风险。 CMV is commonly transmitted among young toddlers and children in day care centers and has reached up to 70% in some day care settings. CMV may also be transmitted from an infected donor to a recipient through transfusion of blood and blood products, and bone marrow and solid organ transplantation. Staff members working in day care and pre-school settings are at increased risk for CMV infection. Nosocomial transmission of CMV to health care workers is uncommon. The CDC has provided the following recommendations for individuals caring for infants and children: 1) Female employees should be educated about CMV and how it is spread, and also hygienic practices, such as handwashing, that reduce the risk of CMV infection. 2) Non-pregnant women of childbearing age who have never been infected with CMV and who are working with infants and children should not be routinely moved to other work situations to avoid CMV infection. 3) Pregnant women working with infants and children should be informed of the risk of getting CMV infection, the possible effects on the unborn child, and appropriate prevention strategies. 4) Routine laboratory testing for CMV antibody (immune protein) in female workers is not currently recommended. However, female workers who are pregnant or planning a pregnancy should be informed that a CMV antibody test can help them assess their risk. Whenever possible, CMV seronegative (without CMV antibodies) pregnant women should consider working in a setting with less exposure to young children. 在幼儿园中CMV传播很常见，某些儿童护理场所传染率甚至可达70%。CMV也可经输血、异体骨髓或器官移植传播。在日间护理中心或幼儿园的工作人员CMV感染的风险会增加。医务人员在院内发生的感染并不常见。美国CDC已经制定了婴幼儿护理工作者预防CMV感染的建议：1）培训女性职员CMV的相关知识，提高卫生意识，养成洗手等卫生习惯，降低CMV感染风险。2）在照顾婴幼儿的职员中，未孕的既往无CMV感染的育龄期女性，为避免CMV感染不应常规被调至其他工作岗位。3）应告知从事照顾婴幼儿工作的孕妇CMV感染的风险，以及可能对胎儿的影响和感染的预防措施。4）目前不推荐女性职员常规进行CMV抗体检测。但是孕妇或计划妊娠的职员进行CMV抗体检测有助于评估CMV感染的风险。CMV血清阴性（无CMV抗体）的孕妇应尽可能的避免与儿童接触频繁的工作。 Clinical Manifestations Guided Medline Search 临床表现 CMV causes a broad spectrum of clinical diseases. It is the major cause of non-Epstein-Barr virus infectious mononucleosis in immunocompetent individuals and is an important cause of disease in immunocompromised individuals including in addition to congenitally infected infants, persons with malignancies, organ transplant recipients and persons with AIDS and other severe diseases that impact on cellular immunity. Major diseases associated with CMV include pneumonia, colitis, esophagitis, hepatitis, central nervous system (CNS) disease including encephalitis and polyradiculitis. Other common manifestations, including leukopenia, adrenalitis and oral ulcers have also been described particularly in persons with AIDS. Reactivation of CMV in persons with AIDS in the pre-HAART (highly active antiretroviral therapy) era not only impacted on the development of CMV-specific diseases but on survival; in persons with advanced AIDS without effective antiretroviral therapy, the presence of CMV in blood is an independent predictor of survival (186, 192). CMV感染的临床表现可有多种型式。在免疫力正常人群，它是除EBV以外引起传染性单核细胞增多症最常见的病毒。在肿瘤、器官移植和AIDS等有细胞免疫缺陷的情况下，CMV是很常见的致病病毒。CMV感染可引起肺炎、结肠炎、食管炎、肝炎和中枢神经系统感染（包括脑炎和多发性神经根炎）。白细胞减少、肾上腺炎和口腔溃疡等，也是它常见的表现，在AIDS患者中更容易出现。在HAART（高效抗逆转录病毒治疗）出现之前，CMV再激活不仅可引起CMV感染相关疾病，还与病人的生存期相关；没有经过有效抗逆转录病毒治疗的晚期AIDS患者， 出现CMV血症是的生存期独立预测指标（186，192）。 Congenital CMV Infection: CMV is a major cause of birth defects affecting approximately 1% (.5 to 2%) of all babies born in the United States and other developed countries. Of those infants congenitally infected, approximately 5% are symptomatic at birth. Infants born with symptoms at birth are at highest risk for developing neurological problems including sensorineural deafness. However, between 5-17% of infants with asymptomatic congenital infection will develop hearing loss (37). Put in other terms, of the approximate 4 million births annually in the United States, 40,000 infants are born with congenital CMV and 8,000 will develop sensorineural hearing deficits or other sequelae associated with their infection. The auditory deficits associated with congenital CMV are not stable, so that infants who have normal hearing in the newborn period may be identified as having hearing loss several years after birth. Infants born small for gestational age with manifestations including petechiae, jaundice hepatosplenomegaly, microcephaly and hearing loss are termed to have cytomegalic inclusion disease and are at greatest risk for having severe long-term neurologic deficits. In such cases, thrombocytopenia is also present in 75% at birth. 先天性CMV感染：在美国等发达国家，CMV是婴儿出生缺陷的主要病因，这可影响到1%的新生儿（0.5%-2%）。5%先天性感染的婴儿，在出生时即有症状，这种婴儿易有并发神经系统功能障碍，譬如感觉神经性耳聋。然而，无症状先天性感染婴儿5%－17％也会出现听力丧失（37）。换句话说，美国每年约有400万新生儿，其中4万出生时就有CMV感染，8000新生儿会因此出现感觉神经性耳聋或其他后遗症。先天性CMV感染引起的听力障碍，可出现于出生时也可出现于数年后。早产儿感染可表现为皮肤瘀点、黄疸、肝脾大、小头畸形和听力丧失，被称为巨细胞包涵体病，易合并严重的长期的神经系统缺陷，此类疾病患儿75%出生时有血小板减少。 Chorioretinitis occurs in approximately 10% of infants with symptomatic congenital CMV. The presence of periventricular calcifications seen on CT scan are typical of congenital CMV and are often associated with severe neurological deficits. However, calcifications may not always periventricular and need not be present for an infant to develop mental retardation or hearing impairment. Findings of microcephaly, periventricular calcifications, an abnormal neurological examination or signs of disseminated infection increase the likelihood of long-term CNS sequelae. Primary CMV infection of the pregnant mother is more likely to be associated with congenital infection. However, women known to be seropositive prior to becoming pregnant are also at risk for having infants born with congenital CMV; the risk in these cases is low, but neurological complications with sensorineural hearing deficits are now well-documented (15). 大约10%有症状的先天性CMV感染患儿会出现脉络膜视网膜炎。头颅CT扫描发现脑室周钙化是其典型的表现，这与严重神经系统功能缺陷相关。然而钙化并不只发生于脑室周围，也不是智力发育迟缓或听力障碍的患儿必有的表现。小头畸形、脑室周钙化、播散性感染的神经系统体征均会增加中枢神经系统后遗症的可能性。孕妇妊娠期间发生原发性CMV感染较易合并婴儿先天性感染。孕前的CMV血清阳性的孕妇引起婴儿先天性感染的风险较小，但也有发生感觉神经性耳聋等神经系统并发症的报道（15）。 Perinatal and Acquired CMV Infection of Children: Healthy infants may acquire CMV infection through exposure to infected maternal genital secretions or postnatally through ingestion of CMV containing breast milk. The incubation period between exposure and symptoms when present is 3 to 12 weeks. Most full term infants exposed to CMV experience asymptomatic infection. However, interstitial pneumonia, paroxysmal cough, petechial rash, hepatosplenomegaly and thrombocytopenia may occur. Hepatitis when it occurs is usually mild and self-limited. Typically, the alkaline phosphatase is elevated out of proportion to the enzyme aspartate aminotransferase (AST) and alanine aminotransferase (ALT). 儿童围产期或后天性CMV感染：接触感染母体的阴道分泌物或进食含有病毒的母乳可引起健康婴幼儿CMV的感染。从感染到出现症状的潜伏期一般为3-12周。足月儿大部分为无症状性的感染，少部分会表现为间质性肺炎、阵发性咳嗽、皮肤瘀点、肝脾大和血小板减少。有些可表现为肝炎，但多症状较轻或为自限性，典型者ALP升高较ALT、AST更明显。 When premature infants acquire CMV infection either through intrapartum exposure, breast milk or transfusion of CMV positive blood products, there is a greater risk of symptomatic infection including interstitial pneumonia, hepatitis, thrombocytopenia, hepatopslenomegaly and hemolytic anemia. Whether CMV infection contributes to the risk for development of chronic lung disease associated with premature remains a topic of debate. Long-term sequelae, however, including mental retardation and hearing deficits have not been associated with postnatal acquisition of CMV. 早产儿可经进食母乳、接触CMV阳性的血液或在产时感染CMV，多为有症状性的感染，其可表现为间质性肺炎、肝炎、血小板减少、肝脾大和溶血性贫血。早产儿慢性肺病是否与CMV感染相关目前观点不一致。长期后遗症如智力发育迟缓、听力障碍等目前没有与产后CMV感染有关的证据。 CMV Infection of Immunocompetent Adults: Symptomatic primary CMV infection of the adolescent or adult usually results in a mononucleosis like syndrome. Wreghitt and colleagues reviewed the clinical presentations of 124 adults with primary CMV infection (4). Of the patients with primary CMV infections, clinical and laboratory findings included abnormal liver function tests in 69%, malaise 67%, sweats 46%, fever 46%, muscle aches 36%, respiratory symptoms 28%, lymphadenopathy 24%, arthralgias 17% and headache 14%. A relapsing illness was reported in 15% of patients and the mean duration of symptoms was 7.8 weeks (range 1-20 weeks). All patients recovered without long-term complications. Of the patients studied by Wreghitt, 15% required hospitalization. In a study of hospitalized patients only diagnosed with CMV disease, Faucher et al. found that 99% of patients were febrile, 51% reported headaches and 36% had splenomegaly (2). The duration of illness in the Faucher study was 21 days. Numerous other clinical syndromes have been associated with CMV infection including Guillian-Barre syndrome, meningoencephalitis, myocarditis, colitis, and Menetrier's disease among others. The causal role of CMV with these other diseases is unclear. 免疫力正常成人的CMV感染：青少年或成人CMV症状性感染主要表现为单核细胞增多症样综合征。Wreghitt等分析124例成人原发CMV感染患者症状及其化验的发现（4），肝功能异常占69%，乏力67%，出汗46%，发热46%，肌肉疼痛36%，呼吸道症状28%，淋巴结肿大24%，关节痛17%，头痛14%。15%患者有复发的感染，症状持续时间平均约为7.8周（1-20周不等）。所有患者均未出现长期并发症。在这组病例中15%需要住院治疗。在Faucher等人对CMV感染住院患者的研究中发现，99%的患者有发热，51%有头痛，36%有脾大（2），平均病程约21天。还有许多临床综合征均报道可能与CMV感染有关，如格林巴利综合征、脑膜脑炎、心肌炎、结肠炎和梅内特里耶病，CMV在这些疾病中的致病机理仍不是很清楚。 CMV Retinitis: Involvement of the retina by CMV was only rarely identified in immunocompetent individuals and was uncommon even in severely immunocompromised persons prior to AIDS in adults (52, 61, 146). Chorioretinitis was most commonly observed in infants congenitally infected with CMV with the cytomegalic inclusion disease syndrome (28). Prior to the availability of HAART, CMV retina was a common complication identified in persons with advanced AIDS (CD4+ lymphocyte counts < 50 cells/µL) (80). Review Article: Golnaz J, Zuravleff J. Retinitis and Endophthalmitis. 2007. CMV视网膜炎：在免疫力正常患者中，CMV感染累及视网膜是很罕见的，即使在AIDS以外的严重免疫缺陷成人患者中也是很少见的（52，61，146）。脉络膜视网膜炎最常见于先天性感染合并巨细胞包涵体病的患儿（28）。在应用HAART治疗以前，CMV视网膜炎还是晚期AIDS（CD4+淋巴细胞计数<50个/uL）常见的并发症（80）。 CMV disease occurred in 21% to 44% of patients with AIDS prior to the introduction of HAART (63, 134). Of patients with CMV disease, approximately 85% had CMV retinitis, especially those with CD4+ lymphocyte counts below 50 cells/µL (178). The introduction of HAART has reduced the incidence of CMV retinitis from 50% to 90% at most centers (88). Twenty-two patients with either a positive CMV PCR in blood or a CD4+ lymphocyte count below 50 cells/µL were followed with monthly eye exams after the initiation of HAART; none developed CMV retinitis after a mean follow up of 14.9 months (199) demonstrating that as the CD4+ lymphocyte count of AIDS patients increases, there is sufficient immune reconstitution to control CMV viremia and prevent development of systemic disease. In a longitudinal cohort study of 1,293 patients without scheduled eye examinations, 53 patients entered the study with CMV retinitis (4%) and only 13 patients (1%) developed retinitis after beginning HAART, of whom 9 had baseline CD4+ lymphocyte counts below 100 cells/µL (215). The highest risk period for identification of CMV retinitis with higher than expected CD4+ lymphocyte counts is within 6 months of initiating HAART; however, since it takes a median time of 6 months between CMV activation within blood and the recognition of CMV retinitis, it is likely that most if not all of these patients had already seeded their eyes prior to immune reconstitution (162). This is further supported by the follow-up of such patients who almost invariably have their retinitis easily controlled with antivirals against CMV. 在HAART出现以前，21-44%AIDS患者有合并CMV的感染（63，134），其中大约85%有CMV视网膜炎，尤其是当CD4+淋巴细胞计数低于50个/uL（178）。采用HAART治疗之后，CMV感染发生率降低了50%-90%（88）。在应用HAART治疗之后，每月进行眼部检查的22例CMV PCR阳性或CD4+淋巴细胞计数<50个/uL的患者之中，随诊了14.9个月，无一例被检查出有CMV视网膜炎的感染（199），表明随诊CD4+淋巴细胞计数的增加，充分免疫重建可控制CMV病毒血症及预防系统性的感染。在1293例患者的纵向队列研究中，有53例（4%）出现CMV视网膜炎，仅13例（1%）在HAART治疗后出现，其中9例CD4+淋巴细胞计数<100个/uL（215）。HAART初始治疗6个月以内是CMV视网膜炎的高危期。由于从CMV激活进入血液到出现视网膜炎一般需要6个月的时间，大部分患者在免疫重建之前已有病毒存在于视网膜（162）。在这些患者，几乎所有的抗CMV病毒药物,能有效的治疗其视网膜炎，这可进一步证实上述的观点。 CMV retinitis can be diagnosed by its appearance on ophthalmologic examination: characteristically, fluffy white retinal infiltrates often with retinal hemorrhages. Without treatment and with continued immunosuppression, retinitis progresses to retinal necrosis and permanent loss of vision, especially when it involves the macula and optic nerve. CMV视网膜炎根据眼科检查可诊断。片状白色视网膜渗出合并视网膜出血是其特征性表现。如不于治疗或其免疫抑制状态的持续存在，视网膜炎可引起视网膜的坏死，尤其是当累及黄斑或视神经时，可导致永久性视力丧失。 Patients with CMV retinitis may have floaters, flashes of light, blurred vision, or blind spots in addition to loss of vision. Mild anterior uveitis, vitritis, and retinal vasculitis may occur. Retinal detachment may be difficult to repair and is associated with poor visual prognosis (62, 136). The use of HAART reduced the risk of retinal detachment related to CMV retinitis in one prospective study by 60%, exerting a larger effect on outcome than standard risk factors for detachment such as large lesion size or anterior location (100). CMV视网膜炎可表现为视野悬浮物感、闪光、视物模糊、视野缺损甚至失明，可伴有轻度前葡萄膜炎、玻璃体炎和视网膜血管炎。视网膜剥离治疗效果较差，多预示严重视力损害（62，136）。一个前瞻性研究发现，HAART可降低大约60%CMV视网膜炎相关视网膜剥离的发生率，HAART对视网膜剥离危险因素，如大面积损伤或前部损害等，其控制效果並不显著，却可防止视网膜剥离的发生（100）。 Lumbosacral Polyradiculopathy and Myelitis: Of the various syndromes that involve CMV in the CNS, CMV polyradiculopathy is the most frequent and characteristic. Patients experience a subacute onset of weakness, loss of reflexes, and variable sensory loss, usually in the legs, in association with bladder and anal sphincter dysfunction (Table 1). Pathologically, there is CMV infection of the ventral and dorsal roots of the cauda equina and often the adjacent spinal cord, with severe inflammation and axonal necrosis. CSF examination typically shows pleocytosis, often with a preponderance of polymorphonuclear leukocytes and hypoglycorrhachia (31). 腰骶部多发性神经根炎和脊髓炎：CMV感染引起多样的中枢神经系统病变表现，多发性神经根炎是最常见也最具其特征性。其表现多为亚急性起病，主要为乏力、腱反射减弱、不同程度和部位的感觉缺失，通常发以双下肢受累为主，伴有膀胱和肛门括约肌功能障碍（表1）。马尾腹侧和后跟及邻近脊髓的CMV感染，同时伴有严重的炎症反应和轴突坏死，是多发性神经根炎的典型病理表现。脑脊液检查主要特点为以多核细胞为主的白细胞增多和糖浓度降低(31)。 CMV Encephalitis: There are two types of CMV encephalitis in patients with AIDS. The first is a diffuse, multifocal, micronodular CMV encephalitis that is difficult to distinguish from dementia complex caused by HIV (3, 59). In a retrospective autopsy study, Holland et al. (82) reported that of 220 autopsies done on patients with AIDS, 14 showed CMV encephalitis and 17 showed HIV dementia without involvement of CMV in the CNS. Both disorders exhibit cognitive and motor disturbances such as confusion, forgetfulness, apathy and withdrawal, unsteadiness, impaired memory, and diffuse hyperreflexia. CMV encephalitis was not associated with typical abnormalities or positive cultures for CMV in the spinal fluid. CMV PCR of CSF is almost always positive and is the diagnostic assay of choice when CMV infection of the CNS is suspected (29, 72, 77, 173, 211). CMV dementia may be associated with serum hyponatremia and signs of Addison s disease. CMV脑炎：有两种临床类型。第一种为弥漫、多灶、小结样病变，有时难与HIV感染相关的痴呆相鉴别(3,59)。Holland等(82)在220例AIDS患者尸体解剖的回顾性研究中发现，14例患有CMV脑炎，17例为HIV性痴呆而不伴有CMV感染。两种疾病都可引起认知和运动障碍如迷惑、健忘、淡漠、退缩、步态不稳、记忆力减退和弥漫的反射亢进。CMV脑炎脑脊液改变並不典型，脑脊液CMV培养的阳性率低，但其CMV PCR 阳性率几乎为100%。因此CMV PCR可作为中枢神经系统CMV感染的诊断性试验(29, 72, 77, 173, 211)。CMV性痴呆可能与低钠血症相关，可能是Addison病的征象。 The second type of CMV encephalitis is CMV ventriculoencephalitis. These patients often have a characteristic ventriculitis demonstrable by magnetic resonance imaging (MRI) with gadolinium enhancement of the periventricular areas (148). Ventriculitis is associated with ependymal and subependymal necrosis. Patients are usually in advanced stages of AIDS, with CD4+ lymphocyte counts below 50 cells/µL. They have acute onset of apathy, disorientation, cranial nerve palsies, and nystagmus, and usually progress rapidly. Ventricular enlargement is usually seen. CSF is usually abnormal, often with a predominance of neutrophils. CMV脑炎的第二种临床类型为脑室脑炎。增强MRI可见特征性的脑室周炎性改变(148)。其主要病理改变为室管膜或室管膜下的坏死。这通常发生于CD4+淋巴细胞小于50/uL的晚期AIDS患者。多见为急性起病，表现为淡漠定向力障碍、颅神经麻痹和眼球震颤，进展较为迅速。影像学检查可见脑室扩大。脑脊液检查可见中性粒细胞为主的白细胞增多。 Mononeuritis Multiplex: CMV mononeuritis, the least common of the CMV CNS disorders, results from focal necrotizing vasculitis of epineural arteries, characterized by polymorphonuclear leukocytic infiltration. Patients present with multifocal or asymmetric sensory and motor deficits in major peripheral or cranial nerves in a setting of severe immunosuppression. Laryngeal nerves may be especially involved (170). This syndrome may coexist with CMV retinitis, polyradiculitis, or encephalitis. Electrophysiologic studies may show axonal neuropathy and CMV DNA is detected in CSF. 多发性单神经炎：多发性单神经炎是由神经弓动脉的局灶性坏死性血管炎引起，病理表现主要为多核白细胞的浸润，是CMV中枢神经系统感染较为罕见的临床症候群。主要临床特点为严重免疫缺陷的患者出现周围神经或颅神经病变，引起多灶性的、非对称的感觉和运动障碍。喉神经受累发生率较高(170)。该综合征可能与CMV视网膜炎、多发性神经根炎或脑炎共同发生。电生理学检查表现为轴突病变，脑脊液CMV DNA 检查可为阳性。 Gastrointestinal Disease: The gastrointestinal tract including the mouth, esophagus, stomach, small intestines, colon, and rectum may be involved with CMV disease in immunosuppressed patients including transplant recipients and persons with AIDS (68). As noted earlier, CMV disease at these sites requires demonstration of the virus as well as local histologic evidence of lesions specific for CMV. Manifestations of CMV include painful erosions or ulcers of the mouth, epiglottis, or pharynx. Odynophagia is a common symptom. The esophagus may be involved with a solitary ulcer or diffuse esophagitis associated with upper gastrointestinal bleeding. Esophageal strictures may occur after healing. Stomach ulcers may cause bleeding, gastric obstruction, or perforation. Involvement of the small bowel includes progressive diarrhea associated with ulcerated necrosis that may be complicated by perforation. Terminal ileal disease may mimic Crohn's disease clinically, and may be associated with massive gastrointestinal bleeding. Patients who have colonic disease may have diarrhea, hematochezia, spasms, and abdominal pain associated with constitutional symptoms such as fever, anorexia, and weight loss. Acute bleeding has been reported, especially from cecal ulcers in transplant patients. The colon may show diffuse ulcerations, focal ulcerations with skip areas, or less commonly pseudopolyps and pseudomembranes. The most common site of gastrointestinal involvement in AIDS patients is the colon, particularly in the rectosigmoid region (44). Hematochezia is seen in a minority of AIDS patients (38, 44). 胃肠道感染：器官移植和AIDS等免疫缺陷患者可出现胃肠道CMV感染，口腔、食管、胃、小肠、结肠和直肠均可受累(68)。CMV胃肠炎确诊需有胃肠道病毒学证据或CMV感染特征性的组织病理的表现。临床上可表现为口腔、会厌或咽部痛性溃疡。吞咽痛是其常见的症状。食管受累可为单一溃疡或弥漫的食管炎，后者可引起消化道出血，治愈后可遗留食管狭窄。胃部主要为溃疡性病变，可引起出血、幽门梗阻或穿孔。小肠受累主要表现为进展性腹泻，可伴有溃疡性坏死甚至肠穿孔。回肠末端病变可引起严重消化道出血，临床上可能与克隆氏病难以鉴别。结肠病变可表现为腹泻、便血、痉挛性腹痛及发热、纳差、消瘦等全身症状。以急性消化道出血起病的病例报道屡见不鲜，常见于伴有盲肠溃疡的器官移植患者。结肠受累可表现为弥漫性溃疡或跳跃分布的局灶性溃疡，假性息肉和伪膜性病变也偶可见到。AIDS患者胃肠道最常受累部位为结肠，尤其是直肠乙状结肠区(44)。便血则在AIDS患者中较少见(38,44)。 The frequency of CMV disease of the gastrointestinal tract in transplant recipients varies from 2% to 15% in various reports (25). It appears to vary with the frequency of CMV disease in general, of which one determinant is the type of transplantation (78). In kidney and liver recipients, the frequency varies from 2% to 6% (85, 97,120, 144). In heart and heart-lung recipients, it is 3% to 16% (97,120, 123). The frequency is even higher in marrow recipients, although specific diagnosis is not always possible because of coexisting graft-versus-host disease (27). 据文献报道，在器官移植患者中，胃肠道CMV感染的发病率从2%-15%不等(25)，与CMV感染总的发病率的变化相匹配，器官移植的类型是其发病率的重要影响因素(78)。在肾脏和肝移植的患者，其发病率为2%-6%(85,97,120,144) 。心脏和心肺联合移植患者，其发病率为3%-16%(97,120,123)。骨髓移植患者，由于常合并移植物的抗宿主病，确诊CMV较为困难。然而据统计，骨髓移植后CMV感染发病率更高(27)。 Central Nervous System Infections: CMV is associated with specific syndromes of the central nervous system (CNS) in patients with AIDS (121). As with CMV retinitis, these syndromes are most common in advanced AIDS when the CD4+ lymphocyte count is below 50 cells/µL and effective antiretroviral therapy is not being administered. 中枢神经系统感染：如前所述，AIDS患者中枢神经系统CMV感染有其特征性的临床表现(121)。同CMV视网膜炎相似，中枢神经系统感染主要发生于未经有效抗HIV病毒治疗而且其CD4 +淋巴细胞小于50个/uL的晚期AIDS患者。 Laboratory Diagnosis Guided Medline Search 实验室检查 The diagnosis of CMV disease is dependent on the disease suspected, the age of the patient and the clinical background. For example, an infant suspected of congenital infection who has CMV detected by any assay within 3 weeks of life can be assumed to be congenitally infected. Similarly, a person with AIDS and a CD4+ lymphocyte count below 50 cells/µL with retinitis diagnosed by an experienced ophthalmologist will almost invariably have CMV retinitis. In contrast, because almost all seropositive immunocompromised persons will reactivate CMV in their urine or saliva, detection of CMV at these sites is not indicative of disease. In many cases a definitive diagnosis requires the identification of CMV in the specific organ involved and the exclusion of other potential pathogens. CMV感染的诊断主要依靠临床表现、发病年龄和其免疫状态。例如，临床符合先天性感染的婴儿若在出生后3周内CMV检测阳性可诊断为先天性感染，同样的，CD4+淋巴细胞计数小于50个/uL的AIDS患者被有经验的眼科医师诊断为视网膜炎的，几乎均是CMV视网膜炎。反之，CMV血清阳性的免疫力正常患者尿或唾液中可检出病毒，但不代表有活动性CMV感染。某些情况下，CMV感染的确诊主要依靠组织中分离出病毒并且要除去其他可能的致病因数。 Serology: Serologic assays are most useful for the identification of past infection; a positive assay for CMV specific IgG indicates previous infection. Conversion from seronegative status to IgM positive is indicative of recent infection, and suggests that an acute illness may be associated with CMV. However, when both CMV IgM and IgG are positive, primary infection from reactivation cannot be definitively determined unless the patient's previous CMV status is known. Although the detection of CMV IgM antibody has been used for the diagnosis of congenital CMV, as many as 30% of infected infants will be CMV IgM negative; false positive IgM assays may also occur. Thus, identification of infectious CMV from urine, antigen detection or detection of CMV-specific nucleic acid is recommended for the identification of a congenitally infected infant. 血清学：血清学检测对既往感染最有诊断意义。CMV-IgG阳性提示既往感染。由血清学阴性转化为CMV-IgM阳性提示近期感染，有助于鉴别某一急性病症是否CMV感染有关。然而当CMV IgG和IgM均阳性时，很难鉴别是原发性感染还是感染的再激活，除非了解患者既往CMV的血清学状态。目前把婴儿CMV IgM 阳性用于诊断先天性感染，但仍有约30%患儿CMV IgM阴性，且也存在一定的假阳性。因此有学者推荐把尿液CMV病毒的检测、抗原测定或CMV特异性核酸的检测用于诊断先天性感染。 Culture: Although culture is still an important tool for the diagnosis of CMV infection, in many situations culture has been replaced by more sensitive tests including antigen detection and nucleic acid detection assays. High titers of CMV are present in the urine and saliva of congenitally infected infants or immunocompromised persons. In such cases, viruses can be isolated in culture within a few days. However, many cultures take from 3 to 6 weeks to demonstrate viral specific cytopathic effect. Cultures of urine, saliva and buffy-coat can be enriched by centrifugation and when combined with immunodetection of CMV using monoclonal antibodies specific for immediate early or early proteins can often result in the detection of CMV in culture within 24-72 hours (66, 139, 149). 培养：病毒培养尽管仍然是很重要的诊断手段，但大部分情况下已经被更敏感的检测方法如抗原检测和病毒核酸的测定所取代。先天性感染或免疫缺陷患者尿液或唾液中病毒含量较高，培养数天即可分离出病毒。然而许多情况下需培养3-6周才能观察到病毒特异的细胞病变效应。采用离心法浓缩病毒以及免疫测定法检测CMV(应用早期或极早期蛋白质单克隆抗体的免疫检测方法)可在24-72小时内获得阳性结果(66,139,149)。 Detection of pp65 Antigen: The use of a monoclonal antibody directed toward the CMV matrix protein, pp65, has been used to detect CMV directly in peripheral blood polymorphonuclear leukocytes (73, 104, 139, 214). This assay is generally more sensitive than culture, is useful for the rapid identification of acute CMV infection, and is commercially available. The quantity of antigen positive cells has been associated with the presence and risk for subsequent development of CMV disease in immunocompromised persons including transplant recipients and persons with AIDS. The major disadvantages to the antigenemia assay are that samples should be processed within a few hours of being obtained and fresh blood must be distributed onto a slide potentially increasing the risk of transmission of an infectious agent to laboratory personnel. pp65抗原的检测：应用CMV基质蛋白pp65的单克隆抗体可检测多形核白细胞中CMV(73,104,139,214)。这一检测方法比病毒培养更敏感，可用于急性CMV感染的快速诊断。目前已有公司提供该检测方法的标准试剂盒。在器官移植或AIDS等免疫缺陷患者，CMV抗原阳性细胞的数量与CMV感染的发病率和感染严重程度相关。抗原检测需要血标本在采集后数小时内进行，对新鲜血进行涂片的操作增加了检测人员感染的风险，这是该检测方法的主要缺点。 Nucleic Acid Detection Methods: A number of different approaches are available for detecting either CMV DNA or RNA in clinical specimens that either amplify the target or probe allowing for high assay sensitivity and specificity. Of these assays polymerase chain reaction (PCR) assays, qualitative or quantitative, are most commonly used (4, 18, 19, 184, 189, 192, 212). PCR is highly sensitive and may detect the presence of CMV in clinical specimens when the risk for development of CMV disease is relatively low. Quantitative PCR assays for CMV have demonstrated that the risk for development of CMV disease increases as the quantity of CMV detected in blood specimens (plasma or cells) increases if no effective antiretroviral therapy is available. Additionally, in persons with untreated AIDS as the quantity of CMV DNA present in plasma increases, there is a concomitant risk not only for the development of CMV disease but also mortality. In fact, in persons with advanced, untreated AIDS (CD4+ lymphocyte counts below 50 cells/µL), the presence and quantity of CMV DNA present in plasma are more predictive of survival than the quantity of plasma HIV-1 RNA (186, 192). Detection of CMV by PCR in cerebrospinal fluid (CSF) is the noninvasive diagnostic procedure of choice for the diagnosis of CMV-related CNS disease (29, 72, 163, 211). 核苷酸的检测：目前有许多方法可用于临床检测CMV-DNA或RNA，通过被检测物或探针的扩增可以达到很高的敏感性和特异性。其中PCR（聚合酶链反应）是最常用的检测方法，即可以定性也可以定量（(4，18，19，184，189，192)。PCR敏感性非常高，临床上即使难以致病的CMV水平也可以检测出来。PCR定量检测表明在未经药物治疗的情况下CMV感染的患病风险随着血浆或细胞内CMV载量的升高而升高。在未治疗的AIDS患者，血浆CMV DNA水平不仅与CMV感染发病率有关而且与病死率明显相关。有研究显示，在未治疗的晚期AIDS患者（CD4＋淋巴细胞小于50个/uL），CMV DNA载量较HIV-1 RNA病毒载量对患者的生存期有更高的预示作用(186,192)。脑脊液CMV PCR检测作为一种无创的诊断试验可用于中枢神经系统CMV感染的诊断(29,72,163,211)。 Pathogenesis Guided Medline Search 发病机理 During natural infection, CMV appears to enter through the epithelium lining the respiratory, gastrointestinal or genitourinary tract. However, infection may also occur through other direct routes including through hematogenous transmission as occurs with transfusion of blood and blood products, and through transplantation of seropositive donor bone marrow and solid organs. During acute infection, CMV can be detected in polymorphonuclear leukocytes and monocytes (35). Currently, the best evidence suggests that CMV establishes latency in myeloid progenitor cells and in endothelial cells of solid organs; the virus can also be detected in circulating monocytes of seropositive individuals. 自然感染中，CMV主要是经呼吸道、胃肠道或泌尿生殖道上皮进入体内。CMV也可经血源性传播，如输血或血制品、骨髓或器官移植等。在急性感染，CMV病毒可在多形核白细胞和单核细胞中检测到(35)。在潜伏感染，目前认为CMV主要寄存在骨髓造血干细胞和实质脏器的内皮细胞，血循环单核细胞内也可检测到。 CMV-specific latency-associated genes have not been clearly identified. Whether CMV establishes true latency or expresses a small number of latency transcripts remains under active investigation. How a cell that is carrying the virus genome but not actively replicating can switch from latency to active replication is also unknown. Remarkably, however, 50% to 100% of CMV seropositive transplant recipients reactivate CMV during immunosuppression which is highest with the greatest immunosuppression and when seronegative recipients receive a transplant from a seropositive donor (78). After primary infection and reactivation in the immuno-compromised host, CMV can be detected in the blood during acute infection. Infectious virus is present in circulating monocytes and polymorphonuclear leukocytes, and viral DNA is present within plasma. CMV dissemination occurs during acute infection and when uncontrolled by the host immune system may spread to virtually all organs. CMV特异的潜伏相关基因目前尚未发现。究竟是确实的潜伏还是小剂量的表达一些潜伏转录物均在研究中。载有病毒基因组的细胞由潜伏状态转化为病毒复制的活化状态的机制目前仍不清楚。血清学阳性的器官移植患者或接受CMV阳性供者器官的患者有50％－100%会出现CMV的再活化，其发生率随着免疫缺陷的加重而升高(78)。免疫缺陷患者在CMV原发性感染或再活化时，血液中可检测到病毒，病毒存在于血循环中的单核细胞、多形核白细胞和血浆中。可见当机体免疫力不能抑制病毒时，其急性感染可引起病毒播散至全身各器官。 Considerable evidence indicates that natural killer cells, humoral antibody responses and cell-mediated immunity all play an important role in the control of CMV infection. However, the fact that almost all major and life-threatening CMV related diseases occur in persons with impaired cellular immunity including transplant recipients and AIDS patients, emphasizes the importance of cellular immunity in controlling acute CMV infection. A striking example of the success of the immune system’s ability to control CMV is demonstrated in persons with advanced AIDS who prior to the availability of HAART frequently developed serious CMV disease. However, the same patients with severe CMV disease when treated with HAART and have elevations in their CD4+ lymphocyte counts above 100-150 cells/µL are able to control their infection without the continued need of anti-CMV therapy (see below). 许多研究表明，自然杀伤细胞、体液免疫和细胞免疫在控制CMV感染中均发挥重要的作用。然而，几乎所有严重的CMV感染均发生于细胞免疫缺陷的患者，这说明细胞免疫在控制急性CMV感染中举足轻重的作用。未采用HAART治疗的晚期AIDS患者易合并严重的CMV感染，经HAART治疗CD4＋淋巴细胞大于100-150个/uL后，不需应用抗CMV药物，CMV感染即可被控制，这也充分说明免疫系统在控制CMV感染中的作用。 SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo 药物在体内体外的敏感性 Single Drug 单药 At present there are three drugs (ganciclovir, foscarnet and cidofovir) and one antisense inhibitor (formivirsen) that are approved for the treatment of CMV retinitis. Of these agents, only ganciclovir and foscarnet are routinely used for treatment of the broad spectrum of CMV diseases and for prevention of disease. Ganciclovir, foscarnet and cidofovir all inhibit the CMV DNA polymerase. 目前批准用于CMV视网膜炎的药物仅有更昔洛韦、膦甲酸、西多福韦和一种反义抑制物（福米韦生，formivirsen）。更昔洛韦、膦甲酸和西多福韦均是CMV DNA 聚合酶的抑制物。其中更昔洛韦和膦甲酸普遍用于各种CMV感染和预防。 Ganciclovir ((9-(1,3-dihydroxy-2-propoxy)methyl)-guanine, DHPG), a nucleoside analog, inhibits CMV and also has activity against other herpesviruses including herpes simplex virus, varicella zoster virus, Epstein-Barr virus and human herpes virus type 8. It is the treatment of choice for CMV, but is also effective in immunocompromised hosts for the prevention and treatment of herpes simplex and varicella zoster infections and in some studies in decreasing the risk of EBV-associated lymphoproliferative disease and in treatment of oral hairy leukoplakia. Ganciclovir is phosphorylated to its monophosphate form by a phosphokinase encoded within the UL97 region of CMV and further phosphorylated to its active triphosphate form by cellular kinases. The effective inhibitory concentration (IC50) of ganciclovir for CMV ranges from 0.3 to 8 µM. Most isolates have an IC50 of 1.5 µM or higher. Peak plasma concentration of ganciclovir after a dose of 5 mg/kg given as a 1-h intravenous infusion is 6.6 µg/mL (4 µM = 1 µg/mL). Trough levels were 1 µg/mL after 11 h (181). The usual dose of ganciclovir for intravenous induction is 5 mg/kg twice daily for 10 to 21 days. Maintenance dose is 5 mg/kg daily. 更昔洛韦（9-(1,3-二羟基-2-丙氧基甲基)鸟嘌呤，DHPG）是一种核苷类似物，可抑制疱疹病毒复制，包括CMV、单纯疱疹病毒、水痘-带状疱疹病毒、EBV和人类疱疹病毒8型。临床上不仅可用于治疗CMV感染，还可用于免疫缺陷患者单纯疱疹病毒、水痘-带状疱疹病毒感染的预防和治疗，还有研究表明更昔洛韦可降低EBV感染引起单核细胞增多症的风险，对口腔毛状白斑病有效。更昔洛韦首先被巨细胞病毒（CMV）编码（UL97基因）的蛋白激酶磷酸化成单磷酸盐，再通过细胞激酶进一步磷酸化成其活化形式三磷酸盐。更昔洛韦对CMV半数抑菌浓度(IC50)为0.3～8μM。大部分病毒株的IC50为1.5μM甚至更高。按5mg/kg剂量缓慢静脉注射1小时可达到的峰浓度约为6.6μg/mL(4μM=1μg/mL)。11小时后谷浓度约为1μg/mL(181)。治疗CMV感染常规剂量为5mg/kg静脉注射，两次/日，疗程为10～21天。维持剂量为5mg/kg/d。 Foscarnet is a pyrophosphate analogue that also inhibits the DNA polymerase of CMV. IC50S (µM) for CMV, HSV-1 and HSV-2, varicella zoster virus and Epstein-Barr virus (EBV) are 50 to 800, 10 to 130, 48 to 90, and less than 500, respectively. Foscarnet penetrates the blood-cerebrospinal fluid (CSF) barrier with a coefficient of 0.05 to 0.72. After a single intravenous infusion of 90 mg/kg, Cmax at steady state is a mean of 623 µM (1 µM equals 0.3 mg/mL). Corresponding CSF levels are approximately two-thirds of plasma levels (74). 膦甲酸是焦磷酸盐类似物，可抑制CMV DNA 聚合酶。对CMV、HSV-1、HSV-2、水痘-带状疱疹病毒和EBV的半数抑菌浓度（μM）分别为50～800、10～130、48～90和＜500。膦甲酸经血脑屏障的渗透系数为0.05～0.72。静脉注射90mg/kg剂量时，稳态情况下的最大血药浓度平均约为623μM（1μM=0.3mg/mL）。脑脊液药物浓度为血药浓度的2/3左右(74)。 Cidofovir (HPMPC, (S)-1-(3-hydroxy-2-(phosphonylmthoxy)propyl) cytosine is a nucleotide analogue that inhibits the CMV DNA polymerase. In vitro, cidofovir has also been found to have activity against VZV, EBV, HSV-1 and 2, and herpesviruses 6,7 and 8, papillomavirus, Molluscum contagiosum virus, adenovirus and poxviruses (including smallpox). The ID50 is 0.5 to 2.8 µM for wild isolates. Cellular enzymes are responsible for serial conversion to the diphosphate form, the active intracellular antimetabolite (77). The diphosphate form has a long intracellular half-life, exceeding 48 h (21). 西多福韦（HPMPC，(S)-1-(3-羟基-2-磷酸甲氧基丙基)胞嘧啶）也是一种核苷酸类似物，可抑制CMV DNA 聚合酶。体外实验显示，西多福韦对VZV、EBV、HSV-1、HSV-2、人类疱疹病毒（6、7、8型）、乳头瘤病毒、触染性软疣病毒、腺病毒和痘病毒（包括天花）等均有抗病毒活性。野生病毒株的半数抑菌剂量（ID50）为0.5～2.8μM。在细胞内酶的作用下转化成双磷酸酯，为有活性的细胞内抗代谢物(77)。双磷酸酯形式在细胞内半衰期较长，大于48小时(21)。 Acyclovir is the most commonly used treatment for infections with herpes simplex virus and varicella zoster virus with IC50S of 0.1 to 0.2 µM for most HSV strains and 4 to 20 µM for VZV strains. Both HSV and VZV encode a thymidine kinase that effectively phosphorylates acyclovir to its monophosphate form which is then further phosphorylated to its active triphosphate form by cellular kinases. CMV does not encode a thymidine kinase and is sensitive to acyclovir at concentrations approximating 100 µM (107, 134) (1 µg/mL acyclovir is equivalent to 4.4 µM). 阿昔洛韦是最常用的治疗单纯疱疹病毒和水痘-带状疱疹病毒感染的药物，对HSV和VZV的半数抑菌浓度分别为0.1～0.2μM、4～20μM。HSV、VZV均能够编码一种胸苷激酶，可把阿昔洛韦磷酸化为单磷酸酯，进一步在细胞内被磷酸化为其活性形式三磷酸酯。CMV不具有胸苷激酶的编码基因，当血药浓度达到100μM（4.4μM=1μg/mL）左右时才有抗CMV作用(107,134)。 The high ID50 of acyclovir for CMV precludes its use for therapy of CMV infections clinically. However, it has been used for prophylaxis against CMV disease in solid organ and bone marrow transplant recipients with some success (but is inferior to both ganciclovir and foscarnet for prevention of CMV disease; see below). 如此高的半数抑菌剂量限制了阿昔洛韦用于控制CMV感染的临床使用。但有临床研究显示阿昔洛韦可预防器官或骨髓移植患者的CMV感染（但疗效较更昔洛韦和膦甲酸较差，见下文）。 Combination Drugs Guided Medline Search 联合用药 Limited research has examined the combination of antivirals against CMV in vitro. Most studies have found that the combination of ganciclovir and foscarnet are usually additive and in some cases synergistic. Similar findings have been found for the combination of cidofovir with either ganciclovir or foscarnet. Clinical treatment approaches examining the combination of ganciclovir and foscarnet have in some settings demonstrated modest benefit of the combination but is associated with additive toxicities. 目前联合用药抗CMV的体外研究资料较少。有研究发现更昔洛韦和膦甲酸联用可增加疗效，甚至有协同作用，西多福韦与更昔洛韦或膦甲酸联用也有类似的效应。临床治疗上也发现更昔洛韦和膦甲酸联用可轻度增加疗效，但药物毒副作用也会增加。 ANTIVIRAL THERAPY Smart search 抗病毒治疗 Drug of Choice Guided Medline Search 药物选择 Ganciclovir:
The drug of choice for the treatment of CMV is
g 更昔洛韦：治疗CMV感染的首先药物。免疫缺陷患者应先诱导治疗（每日两次用药），后给予维持治疗（每日一次用药）(见表2)。静脉途径给药时更昔洛韦几乎全部经肾脏排泄，口服用药约0～85％不能被吸收经消化道排出。肾功能衰竭患者用药需调整剂量（见表3）。 Cerebrospinal fluid levels of ganciclovir range from 24% to 70% of plasma levels with intravitreal concentrations approximating 10% to 15% of plasma levels. Neutropenia is a common complication of ganciclovir treatment occurring in 25% to 40% of those receiving treatment. The neutropenia is usually responsive to granulocyte-colony stimulating factor (G-CSF); however, following bone marrow/stem cell transplantation, ganciclovir may slow engraftment which has made foscarnet the drug of choice for some transplant services. 脑脊液内和玻璃体内药物浓度分别为血药浓度的24～70％、10～15％。粒细胞减少是更昔洛韦的常见副作用，发生率为25～40％，应用G-CSF大部分可纠正，但在进行骨髓移植或造血干细胞移植的患者，更昔洛韦可延缓移植过程，因此进行移植的患者可考虑应用膦甲酸。 In a direct comparison between ganciclovir and foscarnet in the treatment of CMV retinitis in persons with AIDS, foscarnet was as effective as ganciclovir but was associated of greater toxic reactions (178, 179). Of interest, AIDS patients, in one study, treated with foscarnet in the pre-HAART era had a lower mortality than those receiving ganciclovir (perhaps due to the modest antiretroviral activity of foscarnet; see below). 临床研究发现，膦甲酸治疗AIDS患者CMV感染，与更昔洛韦相比同样有效，但副作用较大（178，179）。有趣的是，在HAART出现前，应用膦甲酸的AIDS患者较应用更昔洛韦者死亡率更低（可能与膦甲酸的抗逆转录病毒活性有关，详见下文）。 Oral
Ganciclovir: Until recently the only form of oral
g 口服更昔洛韦：目前更昔洛韦口服剂型的生物利用度仍很低，每日用药3000mg（500mg，每日六次餐后服用），仅6％～9％被吸收。3000mg/日分3～6次服用血药浓度可超过0.5μg/mL（2μM），足以抑制体内大部分CMV病毒株（通常为1g，3次/日，详见表2）。口服剂量大于6000mg/日疗效不再增加，但副作用明显增加。口服给药可降低耐药的发生率，对预防免疫缺陷患者的CMV感染疗效明显（2，185）。 Because high peak titers of ganciclovir are not achieved with the oral preparation, it is not used for initial treatment. Considerable data have demonstrated the efficacy of oral ganciclovir for maintenance therapy for person with AIDS and CMV retinitis and in prophylaxis against CMV disease in persons with AIDS and transplant recipients. 口服给药短期难以达到较高峰浓度，因此不适于初始治疗。但有研究表明作为AIDS 合并CMV视网膜炎的维持用药和AIDS或器官移植患者CMV感染的预防治疗，口服给药疗效确切而显著。 Oral ganciclovir has to a great extent been supplanted by valganciclovir for prophylaxis/pre-emptive therapy and maintenance. In many situations, valganciclovir has replaced intravenous ganciclovir for primary treatment and maintenance. 近来缬更昔洛韦已在很大程度上代替口服更昔洛韦，作为预防或维持治疗用药，甚至在许多情况下已代替静脉更昔洛韦用于初始治疗
Valganciclovir: Valganciclovir is a monovalyl ester prodrug of
g 缬更昔洛韦：缬更昔洛韦是更昔洛韦和缬氨酸的单酯缩合物，是更昔洛韦的前体药物，口服吸收后可被迅速水解为更昔洛韦。从缬更昔洛韦代谢形成的更昔洛韦的生物利用度为60%,一次口服900 mg缬更昔洛韦与静脉给予5 mg/(kg·d)更昔洛韦可达到相似的血药浓度（见表2）。因此缬更昔洛韦可被用于CMV视网膜炎的诱导治疗和维持治疗，并有研究证实口服缬更昔洛韦与静脉用更昔洛韦疗效相当（117）。 Alternative Therapy 备选用药 Foscarnet: Foscarnet sodium is an inorganic pyrophosphate that inhibits replication of CMV as well as other herpesviruses by selective inhibition at the pyrophosphate binding site of virus-specific DNA polymerase. Foscarnet also inhibits the reverse transcriptase of HIV. Unlike most nucleosides, foscarnet does not require phosphorylation by viral or cellular encoded kinases for its activity. Cerebrospinal levels range from 55% to 75% of plasma concentrations. 膦甲酸：膦甲酸钠是一种无机焦磷酸盐，可通过选择性的与病毒特异DNA聚合酶上焦磷酸盐结合位点结合抑制酶的活性，进而可抑制CMV及其他疱疹病毒的复制。膦甲酸也可抑制HIV 逆转录酶的活性。与大部分核苷类抗病毒药不同，膦甲酸不需要病毒或细胞内酶进行磷酸化，即可发挥抗病毒的活性，。脑脊液的药物浓度为血药浓度的55～75％。 Foscarnet requires intravenous induction followed by maintenance therapy, and is associated with a number of potential serious complications. Induction treatment with foscarnet is given as 90 mg/kg intravenously every 12 hrs. Maintenance therapy is 90-120 mg/kg given intravenously daily (Table 2). In persons with AIDS time to retinitis relapse and survival were improved with the 120 mg/kg maintenance dose when compared to the 90 mg/kg dosage (81, 91). Controlled infusion of foscarnet is required with ≤ 24 mg/mL (undiluted) when given by a central line or < 12 mg/mL (diluted in 5% dextrose or saline) via peripheral line. The 90-120 mg/kg dosage should be administered over at least 2 hours via infusion pump. Patients should remain well-hydrated during therapy. The drug is excreted exclusively through the kidneys and patients receiving inadequate hydration have developed cervical or penile ulcers. Foscarnet levels must be adjusted for renal failure ( Table 4). 膦甲酸用法为经静脉诱导治疗和维持治疗，可引起较多潜在的严重副作用。诱导治疗剂量为90mg/kg静脉注射每12小时一次；维持治疗剂量90-120mg/kg静脉注射每日一次（见表2）。AIDS患者应用120mg/kg维持治疗较90mg/kg可获得更长的缓解期和更高的生存率（81，91）。经中心静脉给药药物浓度需≤24mg/mL（未稀释），经外周静脉给药需≤12mg/mL（可用生理盐水或5％葡萄糖稀释）。输注时间需大于两小时。用药期间需充分水化。膦甲酸几乎全部经肾脏排泄，水化不充分可引起颈部或阴茎溃疡。肾功能衰竭时需调整药物剂量（表4）。 Cidofovir: 西多福韦：西多福韦也是一种核苷酸类似物，对CMV等许多病毒均有抗病毒活性。该药半衰期较长（t1/2＝17～65小时），给药间隔长达1周甚至更长。70％～85％经肾排泄。临床前研究发现西多福韦最主要的毒副作用是剂量依赖的肾毒性，可引起近曲小管细胞的变性和坏死（105）。丙磺舒可竞争性被近曲小管重吸收，减少西多福韦的重吸收，动物实验证实丙磺舒可减轻西多福韦的肾脏毒性，因此临床应用西多福韦时必需合用丙磺舒。5mg/kg每周一次次静脉注射是最大耐受剂量（145）。治疗CMV视网膜炎推荐剂量为，诱导治疗：2mg/kg每周一次，应用两次；维持治疗：2mg/kg每两周一次（表2）。用药前3小时应给予丙磺舒2g口服。
Considerable evidence indicates that cidofovir is inferior to either
g 较多临床研究显示，治疗或预防CMV系统性感染西多福韦疗效次于更昔洛韦和膦甲酸。西多福韦清除CMV病毒血症失败是很常见的。应用该药即使能够治愈CMV视网膜炎，仍有发生其他部位CMV感染的风险。 Formivirsen: Formivirsen is an antisense compound with activity against CMV. It is approved for intravitreal injection for treatment of patients with CMV retinitis in whom other treatments are not appropriate because of toxicity or inadequate response (see below). 福米韦生（Formivirsen）：是一种反义寡核苷酸药物，可抑制CMV的复制。当其他药物疗效不佳或不能耐受时，可应用该药玻璃体内注射治疗CMV视网膜炎。 Combinations of Antiviral Agents 抗病毒药物的联合应用
In controlled clinical trials, combination of
g 目前有随机对照临床研究发现，更昔洛韦和膦甲酸联用对治疗单药无效但并未产生耐药的AIDS 患者CMV视网膜炎有效。也有联合用药治疗其他部位CMV感染的报道，例如AIDS患者的CMV胃肠炎和多发性神经根炎。尽管联合应用取得了一定的疗效，但给药时间的延长和毒副作用的增加限制了该方法的使用。 Resistance to Antiviral Agents Used for Treatment and Prevention of CMV CMV的耐药情况
The development of resistance to
g 临床已有对更昔洛韦、膦甲酸和西多福韦的耐药的病例报道，病毒耐药是急性CMV感染患者长期免疫缺陷所不可避免的后果。由于针对耐药病毒进行了大量的研究，目前已确定了耐药病毒的基因型和表型。对更昔洛韦低水平的耐药（8μM＜ID50＜30μM）与CMV UL97区突变有关，该区编码的磷酸激酶，可使更昔洛韦磷酸化而活化，高水平的耐药（ID50＞30μM）与病毒UL97区和UL54区（编码DNA聚合酶）均相关。对更昔洛韦低水平耐药的病毒株仍对西多福韦敏感，高水平耐药的通常也对西多福韦耐药。由于DNA聚合酶突变所致的更昔洛韦和西多福韦耐药的病毒株大多仍对膦甲酸敏感。然而，根据作者的经验，如果患者严重免疫缺陷不改善，对更昔洛韦高水平耐药的病毒数月后也对膦甲酸耐药。目前没有证据表明耐药病毒株致病力较敏感株更弱。 When treating immunocompromised patients with any of the three antivirals approved for the treatment of CMV disease, CMV resistance may develop at a localized site while virus within the circulation or urine remains sensitive. This is particularly true for persons with AIDS and CMV retinitis where although there is viral suppression within blood, retinitis progresses. Genotypic analyses by Smith et al. have demonstrated that in such cases resistant virus can be detected in vitreous or aqueous humor removed from the involved eye (172). 免疫缺陷患者在用上述推荐的药物治疗CMV感染时，即使血液或尿中CMV仍对药物敏感，病灶部位病毒有可能产生耐药。这种情况在AIDS合并CMV视网膜炎的患者尤其常见，病毒血症已经控制，但视网膜炎进行性加重。Smith等人已从此类患者病侧眼内的玻璃体中分离出耐药病毒（172）。 Special Infections 特殊感染 Retinitis 视网膜炎
With treatment prior to the availability of HAART, CMV retinitis could be
arrested or contained but not cured. The time to progression of retinal
lesions could be prolonged from a median of 3 weeks to 180 days or longer
(115, 178) as long as maintenance therapy was continued. There are five
FDA-approved treatments for CMV retinitis (intravenous
g Review Article: Golnaz J, Zuravleff J. Retinitis and Endophthalmitis. 2007. 在HAART应用以前，仅能使CMV感染维持稳定或略缓解，很难治愈。应用药物维持治疗，可使视网膜病变在3周到180天甚至更长的时间内稳定不进展（115，178）。美国FDA推荐五种药物（静脉用更昔洛韦、口服缬更昔洛韦、静脉用膦甲酸、静脉用西多福韦、含更昔洛韦的眼内植入物）用于CMV视网膜炎初始和维持治疗。口服更昔洛韦批准用于维持治疗，玻璃体内注射福米韦生用于补救治疗。补救治疗还可以考虑玻璃体内注射更昔洛韦、膦甲酸或西多福韦。西多福韦玻璃体内注射时应警惕药物相关的低眼压。口服更昔洛韦可降低CMV视网膜炎新病变的出现，和免疫缺陷患者全身性CMV感染。对于CD4+淋巴细胞长期维持在低水平的患者，维持治疗倾向于用缬更昔洛韦来代替更昔洛韦。 Intravenous
Ganciclovir: Prior to the licensure of intravenous
g 静脉用更昔洛韦：在正式推荐用于CMV视网膜炎以前，有许多临床病例报道显示静脉注射更昔洛韦有效(7,58,59,83,84)，同时也发现停药后感染很容易复发，维持治疗有必要长期进行(127)。Spector等人（191）进行的随机对照研究证明了静脉注射更昔洛韦疗效明确。该研究随机把病人分为两组，推迟治疗组（13人）和立即治疗组（22人，5mg/kg每日两次，14天后改为5mg/kg/天维持治疗），结果显示两组分别有10例（10/13）和20例（20/22）病变进展，中位无进展期分别为13.5天、49.5天。尽管在严格的判断病变进展的标准下，更昔洛韦疗效肯定，但治疗的获益非常有限，这也充分表明对于AIDS患者免疫重建在治愈CMV视网膜炎中的必要性。 Intravenous Foscarnet: Foscarnet was evaluated by Palestine et al (138) in a randomized controlled trial in persons with AIDS and CMV retinitis. The mean time to progression was 3.2 weeks in the deferred treatment group compared to 13.3 weeks in patients who received immediate foscarnet induction (180 mg/kg/day divided in three doses) followed by maintenance therapy of 90 mg/kg daily. 静脉用膦甲酸：Palestine等人通过随机对照研究对膦甲酸的疗效进行了评估（138）。推迟治疗组和立即治疗组（180mg/kg/天，分3次静脉注射，90mg/kg/天维持治疗）的中位无进展期分别为3.2周和13.3周。
In a comparative trial of foscarnet versus
g 在HAART出现前，有临床研究发现更昔洛韦和膦甲酸治疗CMV视网膜炎疗效没有明显差异，中位无进展期分别为56天和59天。但是更昔洛韦组死亡率为77%，较膦甲酸组明显升高。两组中位生存期分别为5个月和12.5个月。产生这种差异的主要原因是膦甲酸有一定的抗逆转录病毒的活性，膦甲酸治疗4周和16周时患者CD4+淋巴细胞水平较更昔洛韦组更高也证明这一观点。该研究由美国艾滋病医疗试验机构（ACTG）和艾滋病眼部并发症研究组（SOCA）协作执行。据统计，更昔洛韦组较膦甲酸组更易出现粒细胞减少（34%/14%）。但是膦甲酸组药物注射相关并发症发生率更高（58%/24%），以及更多的男性患者泌尿系症状（56%/16%）、肾毒性和电解质紊乱（13%/6%）。另外，膦甲酸组患者因药物毒性而转到更昔洛韦治疗组的发生率高（46%/11%）。两组癫痫发生率相似（9%/12%）。研究发现药物毒性基本可逆，没有导致持续后遗症和死亡（180例）。尽管膦甲酸治疗AIDS CMV视网膜炎与更昔洛韦疗效相当，甚至可降低死亡率（尚缺乏进一步研究证实，与HARRT联合应用其抗逆转录病毒作用可忽略），但由于其较大的毒副作用和临床给药相对繁琐，大部分医疗机构常把更昔洛韦作为AIDS并发CMV视网膜炎的首选用药。 Intravenous
Cidofovir: 静脉用西多福韦：西多福韦是第三个被批准用于治疗CMV视网膜炎的药物，当时已有多种核苷酸逆转录酶抑制剂类抗病毒药物逐步在临床使用，如奈韦拉平等。Lalezari等人(106)进行的随机对照研究显示推迟治疗组和立即治疗组的中位无进展期分别为22天和120天，然而应用西多福韦的患者约24%因尿蛋白超过2+或血清肌酐大于2mg/dl被迫停药。另一项临床研究中，对推迟治疗和诱导治疗（5mg/kg每周一次，应用两周，并续以维持治疗）的疗效进行了比较，并把诱导治疗又分为低剂量维持治疗组（3mg/kg每周一次）和大剂量维持治疗组（5mg/kg每周一次），结果与Lalezari的研究相似。两项研究中，为了降低西多福韦的肾毒性，每次给药时均同时应用了丙磺舒（5mg/kg）。
Although cidofovir has been found to be useful for the treatment of CMV
retinitis and has the advantage of infrequent dosing, failure of the drug to
clear viremia and the high risk of nephrotoxicity have generally resulted in
cidofovir being second line therapy behind
g 尽管西多福韦疗效明确、不需频繁给药，但由于病毒血症清除率低，肾脏毒性明显，通常把西多福韦作为治疗CMV视网膜炎的二线药物。静脉应用西多福韦可引起虹膜炎和眼压降低，甚至视力损害，出现该并发症应及时停药并换用其他抗病毒药物(34)。 Combination
of Ganciclovir and Foscarnet: In situations where a single anti-CMV agent
has failed, the combination of
g 更昔洛韦和膦甲酸的联用：当单药治疗无效时，更昔洛韦和膦甲酸联合治疗可能有效。在HAART出现前，对一组AIDS合并持续活动性或复发性CMV视网膜炎的患者进行的临床研究发现，更昔洛韦治疗组（10mg/kg/天维持治疗）、膦甲酸治疗组（120mg/天维持治疗）和更昔洛韦与膦甲酸联合治疗组（膦甲酸90mg/天，更昔洛韦5mg/kg/天）三组的生存率无明显差异(178,179)，视网膜炎中位无进展期分别为2个月、1.3个月和4.3个月。有趣的是，两种药物交替较单一药物治疗并不能改善疗效，这也进一步说明病毒耐药不是所有CMV视网膜炎病例复发的原因。 In the SOCA study described above, the combination group also had the lowest rate of change in retinal area involved by CMV and visual field loss. Combination therapy was superior and was not associated with more toxic effects than either monotherapy. 艾滋病眼部并发症研究组（SOCA）进行的上述研究中，联合治疗组视网膜病变较轻，视野缺损发生率更低。联合治疗疗效更优，而且毒副作用并没有增加。 However, combination therapy had the greatest negative impact on quality-of-life measures. It was associated with more frequent treatment changes and longer infusion times than the monotherapies. 然而，联合治疗给生活质量带来了负面影响，这主要与注射时间延长和给药频繁有关。 In conclusion, the combination of ganciclovir and foscarnet demonstrated superior suppression of CMV retinitis in persons with advanced AIDS prior to the availability of HAART. The disadvantages of the combination therapy including inconvenience, higher cost and less patient acceptance have made it an uncommon combination except in severely debilitating or life-threatening infections where monotherapy has failed. With the recent availability of valganciclovir, it is possible that the combination of foscarnet and ganciclovir (using valganciclovir) will become a more popular first line therapy in certain life-threatening or high-morbidity CMV infections when the patient can take oral medication. However, with the availability of HAART, the combination of ganciclovir treatment with effective antiretroviral therapy will lead to treatment success in most cases of retinitis. 总之，在HARRT应用之前，联合用药治疗CMV视网膜炎疗效更显著。由于其应用不方便、费用较高，大部分患者不愿接受联合治疗，因此除非严重或危及生命的感染，联合用药并不常规应用。近期新药缬更昔洛韦的使用，使膦甲酸和更昔洛韦（用缬更昔洛韦代替）联合应用成为危及生命或高死亡率CMV感染的首选治疗。然而，随着近年HARRT的临床应用，更昔洛韦联合抗逆转录病毒治疗使大部分CMV视网膜炎能够有效控制。
Oral
Ganciclovir as Maintenance Treatment: Despite the low bioavailability of
oral
g 口服更昔洛韦作为维持治疗：尽管更昔洛韦口服生物利用度较低，但对于HAART出现前的AIDS患者，有资料表明口服药物可用于CMV视网膜炎的维持治疗(47,137,185)。有临床研究发现口服或静脉给药患者的中位无进展期相似。然而也有研究认为静脉药物较口服制剂疗效更好。但口服制剂用药方便、副作用较小，仍是病情稳定患者维持治疗最常用的。口服更昔洛韦同静脉制剂一样，腹泻和粒细胞减少是其常见副作用。
Valganciclovir: Valganciclovir is a monovalyl ester prodrug of
g 缬更昔洛韦：是更昔洛韦和缬氨酸的单酯缩合物，是更昔洛韦的前体药物，口服吸收后可迅速水解为更昔洛韦。药物经水解后其药代动力学与更昔洛韦相同。由缬更昔洛韦转化为更昔洛韦的生物利用度为60%(96,117)。口服900mg缬更昔洛韦可获得与静脉注射5mg/kg更昔洛韦相似的药物浓度。近期有临床研究显示口服缬更昔洛韦（900mg，每日两次，三周后改为每日一次维持）与静脉注射更昔洛韦（5mg/kg首剂，5mg/kg每日一次维持治疗）疗效相当，副反应也无明显差异。对能够口服药物的患者，缬更昔洛韦正逐渐取代静脉注射更昔洛韦用于治疗CMV感染，除非患者肝功能异常或缬更昔洛韦体内代谢变异，口服缬更更昔洛韦已逐步取代口服更昔洛韦来用于维持治疗以及预防治疗。 Intraocular
Administration of Drugs: Intravenous therapy with currently approved drugs
against CMV retinitis is complicated by a high frequency of side effects, the
inconvenience of intravenous administration, and high cost of administering
daily intravenous drug. Experience with local therapy has accumulated since
intraocular injection of
g 玻璃体内注射药物：静脉应用抗CMV药物副作用较多，给药不方便，治疗费用高，使CMV视网膜炎的治疗难以实施。1987年即有更昔洛韦玻璃体内注射的报道(56,75)，目前局部治疗已累积了一定的临床经验。最初玻璃体内注射的药物剂量为更昔洛韦钠0.1ml（200ug）、膦甲酸0.05ml（1.2mg）或膦甲酸0.1ml（2.4mg）。现在常用浓缩更昔洛韦钠溶液（0.1或0.05ml中含更昔洛韦钠2000ug）玻璃体内注射，临床应用安全，疗效明确(214)。诱导治疗通常为每周两次，应用2～3周后每周一次维持治疗。 Another approach to the intraocular administration of ganciclovir has been the placement of a commercially available intravitreal device, which consists of diffusion cells lined by permeable polyvinyl membranes and contains ganciclovir that is surgically implanted into the vitreous. Using this approach, CMV retinitis can be successfully controlled (116, 129, 178). In the pre-HAART era, times to retinitis recurrence were significantly prolonged using the intravitreal implants when compared to any other treatment modality in patients with advanced AIDS. Whereas the median time to progression with the intravenous formulation was found to be approximately 70 days, retinitis progression occurred after 220 days in two studies administering 1 µg/ml through intravitreal implants. Of note, however, the risk of developing retinitis in the uninvolved eye or other systemic CMV disease was lower in advanced AIDS patients receiving intravenous ganciclovir than those with the implant. For this reason in patients who remain immunocompromised, systemic ganciclovir should be administered concomitantly with the implant to prevent the development of CMV disease at a new site. With HAART, patients who respond to their HIV therapy with an increasing CD4+ cells count above 100 cells/ µL may not require systemic therapy. 应用商品化的玻璃体内植入剂是另一种玻璃体内用药的方法。该剂型为有通透性的聚乙烯膜所构成的多孔腔结构，于孔腔内填充更昔洛韦，经手术把药物植入病人的玻璃体内。该治疗方式已成功的在临床上应用 (116,129,178)。在HAART出现前，玻璃体内植入剂与其他治疗方式相比，明显延迟了视网膜炎的复发。研究显示，应用玻璃体内植入剂的中位无进展期为70天左右，其中有两项临床研究报道220天后才进展CMV病变的病例。但是，对于晚期AIDS患者，静脉应用更昔洛韦可降低健侧眼视网膜炎及其他部位CMV感染的风险。因此存在深度免疫缺陷的视网膜炎患者，为防止其他部位CMV感染，在眼内植入药物的同时，应给予全身的CMV治疗，经HAART后，CD4+淋巴细胞升高大于100个/μL的患者则可仅予局部治疗。
Intravitreal 玻璃体内注射西多福韦已被用于治疗AIDS合并CMV视网膜炎。HAART出现前，10mg单剂注射后，其视网膜炎中位无进展期约为55天，优于更昔洛韦或膦甲酸全身用药。多次注射可以进一步延缓疾病进展时期。玻璃体内注射西多福韦后约35%出现轻中度虹膜炎，眼内压降低偶可见到，目前临床上尚不推荐玻璃体内注射西多福韦治疗CMV视网膜炎。 Formivirsen:
Intravitreal formivirsen injection is approved for use in patients with CMV
retinitis in whom other treatments are not appropriate because of toxicity or
inadequate response. CMV replication is inhibited by an antisense mechanism,
suggesting that formivirsen injections may be useful against strains with
phenotypic resistance to
g 福米韦生：玻璃体内注射福米韦生被批准用于因副反应不能耐受其他治疗或难治性CMV视网膜炎患者。福米韦生通过抑制RNA表达发挥抗病毒作用，可用于对更昔洛韦、膦甲酸或西多福韦耐药病毒株的治疗。诱导治疗为330μg玻璃体注射每两周一次，应用两次，后以330μg玻璃体注射每四周一次维持治疗(133)。最常见的副反应为眼内炎症反应和眼内压升高。福米韦生是第一个批准用于抗病毒的反义药物，但是临床应用经验较少，目前已停产。 In summary, intraocular administration of antivirals is effective in controlling CMV retinitis. The advantage is that a high concentration of drug is delivered locally while avoiding the toxicity of intravenous drug therapy and the inconvenience of intravenous drug catheters. The disadvantages of local therapy are that the treatment does not prevent development of retinitis in the other eye or of CMV disease elsewhere in the body. For patients in whom systemic antiviral therapy is inadequate to control progression of the retinitis, combined therapy with a ganciclovir-containing intraocular device and either oral ganciclovir (115) or oral valganciclovir would seem to be the best strategy to provide highly efficacious control of the retinal infection while reducing risk of systemic disease or second eye involvement. Choice of initial therapy for CMV retinitis is a multifactorial decision that incorporates the patient’s immune status and prior history of antiretroviral therapy (114). Patients who are HAART naïve or recently started on HAART have an excellent chance of responding to therapy with oral valganciclovir alone without the need for intravitreal therapies. Patients with retinitis progression while taking systemic anti-CMV therapy should be rapidly moved to intravitreal therapy. 总之，玻璃体内注射药物治疗CMV视网膜炎疗效明确。其优点是局部药物浓度较高，但毒性副作用较轻，并可避免静脉用药时留置静脉导管所引起的不便。其主要缺点为不能预防其他部位的CMV或另一侧眼的感染。对全身用药后病变仍进展的病例，更昔洛韦眼内植入剂联合口服更昔洛韦(115)或缬更昔洛韦应该是最佳治疗措施。其既有助于视网膜炎的控制，又可以避免CMV系统性感染或另一只眼受累。CMV视网膜炎初始治疗的选择取决于多种因素，如患者的免疫状态和既往抗病毒治疗情况(114)。未经HAART或近期开始HAART的患者，仅口服缬更昔洛韦通常可以控制病情，不需要玻璃体内注射治疗。而全身用药病情仍有进展的患者应尽快采用玻璃体内注射疗法。 CMV Retinitis in the HAART Era HAART时代的CMV视网膜炎 With the availability of effective antiretroviral therapy, the patient with AIDS and a CD4+ lymphocyte count below 50 cells/µL has the opportunity to significantly lower their viral load and increase their CD4+ cells. Considerable data indicate that maintenance therapy for CMV retinitis can be safely discontinued when patients have quiescent retinitis and CD4+ lymphocytes have risen above 100-150 cells/µL for at least 3 months (32, 197, 202, 204). It is essential that all patients who have their CMV maintenance therapy discontinued have their CD4+ lymphocyte count monitored routinely as part of their HIV/AIDS care and undergo regular ophthalmologic examinations to ascertain that the retinitis remains inactive. A syndrome associated with immune reconstitution in patients with CMV retinitis, immune uveitis, has been described (98, 130, 182). In such cases of immune activation, anecdotal reports of systemic and periocular corticosteroid therapy have been useful in controlling the uveitis. CMV maintenance therapy should be reinstituted with any recurrence of CMV retinitis without regard to lymphocyte count or when CD4+ lymphocytes have declined below 100 cells/µL. CD4+淋巴细胞计数低于50个/µL的AIDS患者经抗逆转录病毒治疗后，多能够使病毒载量明显的降低和CD4+淋巴细胞明显升高。有足够的数据表明，当CD4+细胞大于100-150个/µL持续3个月以上并且视网膜炎不活动时，停用维持治疗后很少有CMV视网膜炎的复发(32,197,202,204)，但这需规律的监测其CD4+细胞计数，以及定期的进行眼科检查。免疫性葡萄膜炎是CMV视网膜炎患者免疫重建后引起的一种综合征（98，130，182），有文献报道针对这种免疫重建综合症给病人以全身或眼周应用激素治疗是有效的。当视网膜炎复发或CD4+细胞小于100个/µL时应给病人继续维持治疗。 Lumbosacral Polyradiculopathy and Myelitis 腰骶部多发性神经根炎和脊髓炎
Although there have been no controlled trials, clinical improvement has been
reported after induction and maintenance therapy with intravenous
g 尽管缺乏对照研究，但有临床资料表明静脉应用更昔洛韦诱导和维持治疗可能有效（31，36，101）。对16例多发性神经根炎研究发现（31），其中6例经更昔洛韦治疗临床症状好转并稳定的维持。治疗反应不佳的，主要与以下因素有关：脑脊液多核白细胞升高、脑脊液葡萄糖水平降低、治疗前严重下肢瘫痪（36）。抗CMV治疗期间发病的治疗反应差。疗效不佳主要是与神经系统不可逆性损害和病毒的耐药有关（209）。膦甲酸或膦甲酸和更昔洛韦联用与更昔洛韦单药疗效相似。根据作者的经验，除非依据典型的临床症状结合脑脊液CMV DNA PCR阳性在几天内作出诊断，多数患者将是病情稳定，但没有明显的改善。 CMV Encephalitis CMV脑炎
Treatment of AIDS patients with CMV encephalitis with either
g 应用更昔洛韦和（或）膦甲酸治疗AIDS合并CMV脑炎患者，治疗反应差异较大。有报道更昔洛韦可使影像学改善和CMV血清学转阴，但神经系统症状改善不明显（148）。Salazar等人（157）对5例CMV脑室炎患者进行了研究，其中4例进行了尸检。3例应用更昔洛韦治疗， 2例应用膦甲酸治疗。1例患者经更昔洛韦治疗4周后临床症状和MRI表现均有明显改善。更昔洛韦治疗的另外2例及膦甲酸治疗的2例患者均病情恶化死亡。晚期AIDS患者在应用更昔洛韦或膦甲酸维持治疗CMV视网膜炎过程中，即使视网膜炎得以控制，也有可能发生CMV脑炎（11）。同多发性神经根炎相似，提高对该病警惕、早期行PCR检测、早期治疗对改善患者预后至关重要。 Mononeuritis Multiplex 多发性单神经炎
Temporary relapse or improvement of neuritis may follow
g 更昔洛韦或膦甲酸治疗后，神经炎可有暂时的复发或改善（156）。 Cytomegalovirus Pneumonia CMV肺炎
The lung is one of the most common sites of CMV disease. CMV pneumonia may
result from different mechanisms of pathogenesis. Hence the treatment of CMV
pneumonias differs, depending upon the type of patient. CMV pneumonia has been
described rarely in immunocompetent patients, in association with CMV
mononucleosis (116). The mortality of this condition is negligible, and
antiviral therapy is highly effective (although usually not necessary). The
most severe type of pneumonia with the highest mortality occurs in bone marrow
recipients. Untreated, the mortality is 70 to 85% (124). Used alone,
g 肺部是CMV感染最常见的受累部位之一。CMV肺炎的发病机制有多种类型，因此根据不同类型致病机制，采用不同的治疗。CMV单核细胞增多症相关的CMV肺炎在免疫健全的患者是很少见的（116），此种情况的病死率是非常小的，而且有非常好的抗病毒治疗果效（尽管大部分情况下不需要）。最严重和死亡率最高的CMV肺炎类型，常见于骨髓移植患者。若不治疗，死亡率可达70-85%（124）。应用单药更昔洛韦可降低病毒载量但不能降低死亡率。目前临床广泛采用更昔洛韦和免疫球蛋白联合疗法（53，152）。Reed等（152）报道更昔洛韦与免疫球蛋白联用可降低死亡率，该研究中联合治疗组10例患者死亡率为30%，而更昔洛韦或免疫球蛋白单药治疗组11例患者无一例存活。患者病程有多种表现：部分病人治疗14天后病症缓解，部分病人仍有症状需维持治疗，还有些病人病症缓解后复发，需重新诱导治疗。粒细胞减少是更昔洛韦反复使用常见的副反应（151，152），通常给予G-CSF治疗有效。 In conclusion, CMV pneumonia in marrow recipients is highly fatal if left untreated. Neither ganciclovir or immune globulin alone is effective treatment. Mortality has been reduced by the combination but is still significant. For this reason, prophylaxis/pre-emptive therapy is preferable than treating CMV pneumonia in this population. 总之，骨髓移植患者并发CMV肺炎若不治疗死亡率极高。单用更昔洛韦或免疫球蛋白均无效，尽管两者联用有效，但死亡率仍然很高。因此，针对骨髓移植等人群，可予预防治疗或抢先治疗，避免CMV肺炎的发生。 In solid organ transplantation, the course and treatment of CMV pneumonia is less well documented. Mortality varies for different types of transplanted organs, from 48% in an early series of renal recipients (144) to 75% in heart and heart-lung recipients (50). More recent data suggest that mortality associated with CMV pneumonia is generally lower in solid organ recipients than in bone marrow recipients (94, 161) likely due to the level of immunosuppression among the different groups of transplant recipients. Duncan et al. (51) reported that 48% of a group of 124 lung recipients developed CMV pneumonia. The ganciclovir-treated group had a significantly higher 1-year survival than the untreated group (86% vs. 38%). However, survivors had clinically significant chronic complications, compared with those who did not have CMV pulmonary infection. The need for immune globulin addition has not been documented in solid organ recipients remains controversial, although the combination has been reported effective in anecdotal reports (33, 65 and see below). 实质脏器移植患者中CMV肺炎的病例报道及治疗经验相对较少。不同器官移植患者CMV肺炎的死亡率各不相同，肾脏移植约为48%（144），心脏和心肺联合移植约为75%（50）。近年来有文献报道实质脏器移植患者CMV肺炎的死亡率普遍较骨髓移植患者低，可能与不同器官移植患者免疫状体不同有关（94，161）。Duncan等（51）报道了124例肺移植患者，约48%并发CMV肺炎，其中更昔洛韦治疗组较对照组（未治疗）1年生存率明显提高（86%与38%），然而，存活者较未发生CMV肺炎的肺移植患者有更多的慢性并发症。尽管已有病例报道更昔洛韦与免疫球蛋白联用有效，但在实质器官移植患者中是否需用免疫球蛋白治疗仍存在争议(33,65)。 Despite the common occurrence of CMV disease and infection of the lungs demonstrated at post-mortem in persons with AIDS, CMV pneumonia is uncommon. The infrequency of CMV pneumonia associated with AIDS even prior to the availability of HAART likely reflects differences in the pathogenesis of CMV pneumonia in AIDS patients in comparison to the pneumonia observed following transplantation. Whereas CMV pneumonia following transplantation reflects infection of the lung with a concomitant local immunologic response often temporally associated with graft versus host disease, CMV pneumonia in persons with AIDS is the result of overwhelming infection with CMV (76, 128). 尽管AIDS患者在尸检中CMV感染很常见，即使在HAART出现前，AIDS并发CMV肺炎也很罕见，这说明了AIDS患者与器官移植患者发生CMV肺炎的机制有所不同。 移植患者并发CMV肺炎不仅体现肺部感染后局部的免疫反应，还与移植物抗宿主病有关。AIDS患者并发CMV肺炎则完全是由CMV感染引起的炎症反应(76,128)。 In persons with AIDS, CMV is frequently present in association with other opportunistic pathogens especially Pneumocystis carinii. Treatment of Pneumocystis alone frequently results in clinical improvement without the need to treat the CMV (20, 92, 95) . However, numerous reports in the pre-HAART era documented cases of CMV pneumonia in persons with AIDS (6, 45, 67, 193, 201) so that the diagnosis must be considered in patients with advanced AIDS who are not responding to traditional antimicrobial therapy for Pneumocystis carinii and common bacterial pathogens (122). AIDS患者中，CMV感染通常与其他机会致病菌，尤其是肺孢子菌感染合并存在。一般而言单纯给予治疗肺孢子虫肺炎后其临床症状即可缓解，这无需抗CMV的治疗(20,92,95)。HAART出现前，有许多AIDS患者CMV肺炎的病例报道(6,45,67,193,201)，因此对经抗肺孢子菌和抗细菌治疗无效的病例需要考虑CMV肺炎(122)。 Gastrointestinal Disease 胃肠道感染
In an anecdotal report of
g HAART出现前，对41例应用更昔洛韦治疗的AIDS合并CMV胃肠炎患者随诊观察发现，其中30例临床症状有好转，32例有病毒学改善（25）。有学者对AIDS合并CMV结肠炎患者进行了随机对照研究，治疗组应用更昔洛韦治疗（10mg/kg每天，疗程14天），对照组应用安慰剂，研究发现治疗组结肠及尿CMV培养阳性率较对照组明显降低，治疗组临床改善患者占63%,对照组为33%（41）。对照组患者体重明显降低，但治疗组无下降。两组患者中腹泻的缓解率，基本上是相似的。 In additional anecdotal reports, AIDS patients with CMV gastrointestinal disease who failed ganciclovir therapy (defined as progression of CMV disease) benefited from foscarnet. Dieterich et al. (42) administered foscarnet to 19 such patients and observed histopathologic improvement in 67% and clinical improvement in 74%. In a randomized comparison of the two drugs, no difference was observed between ganciclovir and foscarnet in treatment of gastrointestinal disease (12). Survival in both treatment groups (in the pre-HAART era) was less than 40 weeks and was unaffected by maintenance treatment therapy. Thus either ganciclovir or foscarnet was effective as first-line treatment for gastrointestinal CMV disease. Maintenance therapy did not prevent progression of the disease. The combination of ganciclovir and foscarnet has also been used successfully for treatment of CMV gastrointestinal disease (43). 有非对照研究报道，更昔洛韦治疗失败的CMV胃肠炎（指CMV感染进展）可有效的应用膦甲酸来治疗。Dieterich等（42）用膦甲酸治疗了19例此类患者，组织病理学改善率和临床改善率分别为67％和74％。对两种药物进行的随机对照研究显示两者疗效并无明显差异，生存期均低于40周（HAART出现前），维持治疗不能延长其生存期（12）。因此两者均可作为CMV胃肠炎的一线治疗，但维持治疗不能防止其病情进展。也有更昔洛韦联合膦甲酸治疗CMV胃肠炎成功的报道（43）。 Ganciclovir therapy in case reports resulted in symptomatic improvement of gastrointestinal CMV disease in as many as 93% to 100% of solid organ transplant recipients (97,120). Mayoral et al. (120) used ganciclovir to treat 14 solid organ transplant recipients with gastrointestinal CMV disease (all but one endoscopically proven); 13 improved, 4 required additional treatment for recurrent disease. Kaplan et al. (101) reported that gastrointestinal disease was the most common infection in heart and heart-lung transplant recipients. An incidence of 9.9% included gastritis, 9;gastric ulceration, 4;duodenitis, 3;esophagitis, 1;pyloric perforation, 1;and colonic hemorrhage, 1. They were treated with ganciclovir 5 mg/kg twice daily for 2 to 8 weeks. Relapses occurred in 4 of 9 patients who were followed for a median of 18 months. 根据文献报道，更昔洛韦治疗实质器官移植患者的CMV胃肠炎，临床缓解率可达93％－100％（97，120）。Mayoral等人（120）应用更昔洛韦治疗了14例并发CMV胃肠炎（13例经内镜检查确诊）的实质器官移植患者，13例有病情的缓解，其中4例因复发需再次治疗。Kaplan等（101）对一组心脏和心肺移植患者进行了研究，发现CMV胃肠炎在该组病例是最常见的CMV感染，约占移植患者9.9％，包括胃炎9例、胃溃疡4例、十二指肠炎3例、食管炎1例、幽门穿孔1例、结肠出血1例。给予更昔洛韦治疗（5mg/kg每日两次，疗程2-8周）后，患者平均随诊18个月，9例中有4例病情复发。 Reed et al. (153) conducted a controlled trial in marrow recipients who had gastrointestinal CMV disease; 14 patients were treated with ganciclovir and 19 received placebo. The most common involvement was the esophagus. Ganciclovir was given at a dosage of 2.5 mg/kg every 8 h for 14 days. No patient had resolution of all symptoms after treatment with ganciclovir. Partial improvement was observed in both treated and placebo control groups. The only significant difference was virtual elimination of the virus from both systemic and local cultures in the treated group; 73% of the treated and 79% of the placebo group showed some improvement. This study showed no clear advantage of treatment, although higher doses of ganciclovir (i. e. 5 mg/kg twice daily) may have demonstrated an advantage. Reed等（153）对33例合并CMV感染的骨髓移植患者进行了对照研究，14例应用更昔洛韦治疗（2.5mg/kg,每8小时一次，疗程14天），19例应用安慰剂治疗作为对照组。这组患者中最常见的感染部位是食管。应用更昔洛韦治疗的患者没有一例病情完全缓解。治疗组和对照组中均有患者病情部分缓解。两组患者较明显的差别主要体现在治疗组全身各系统和局部病毒培养阳性率更低，分别为73%、79%。尽管有研究认为更高剂量更昔洛韦治疗（5mg/kg，每日两次）CMV胃肠炎有效，但该试验并没有发现其有效性。 Hepatitis 肝炎
Tissue invasive CMV disease in any immunocompromised host can manifest as CMV
hepatitis. In liver transplant recipients however, CMV hepatitis occurs in
2-17% of the patients and is the most common organ specific manifestation of
CMV infection (107a, 161a).Virtually
all patients with CMV hepatitis have viremia. However, CMV viral load or
antigenemia levels may be variable ( CMV肝炎在免疫缺陷患者侵袭性CMV感染中很常见。肝脏移植患者中CMV肝炎发生率为2-17%，是CMV感染最常受累的器官（107a，161a）。几乎所有CMV肝炎患者均有病毒血症，但病毒载量及血中病毒抗原水平变化较大（107a）。确定诊断需肝脏组织CMV病毒检测阳性（免疫组化法或原位杂交法）。组织病理检查中病毒包涵体少见。肝细胞气球样变和微脓肿是最常见的组织病理表现，但不是CMV感染特异的表现（107a）。绝大多数病例中，CMV肝炎仅是孤立脏器受累的表现，这并不代表播散性感染。
推荐治疗方案为更昔洛韦静脉注射5mg/kg每日两次，疗程2-4周（146a）。CMV病毒血症的患者应至少用药至病毒血症转阴后1周。能够口服药物病情较稳定的患者可考虑应用缬更昔洛韦。应用缬更昔洛韦治疗移植患者组织侵袭性CMV感染如CMV肝炎的病毒学转阴率和临床缓解率与静脉注射更昔洛韦疗效相似（86a）。目前不推荐抗病毒治疗的同时常规加用CMV免疫球蛋白，但在严重胃肠道疾病或球蛋白减少的患者中可考虑应用（146a）。
Liver transplant recipients with CMV hepatitis were at a higher risk for the
subsequent development of biliary complications ( 肝脏移植后出现CMV肝炎容易合并胆道并发症（107a），但恰当治疗仍可获得长期的效果。 Congenital CMV Infection 先天性CMV感染
There are currently no accepted preventive or therapeutic measures for infants
congenitally infected with CMV. Anecdotal trials (131) and a study done
through the Antiviral Collaborative Study Group have suggested for infants
born with symptomatic congenital CMV that the administration of
g 目前尚无有效预防或治疗婴幼儿先天性CMV感染的措施。有小样本非对照临床试验（131）和ACSG组织的研究表明应用更昔洛韦治疗（8-12mg/kg/d，分两次静脉注射，疗程6周）症状性先天性CMV感染患儿可降低听力缺陷的发生率（203及尚未发表数据）。尽管有必要进一步研究证实，但许多专家认为在患儿最初的6-12个月应用更昔洛韦足疗程治疗可显著降低后遗症的发生率。但是，必须有随机对照研究证实该方法的疗效后才会推荐到临床上来使用。 A recent study using hyperimmune CMV immunoglobulin found that there appeared to be benefit of high titer CMV globulin in reducing the expected sequelae associated with congenital CMV. However, the study was uncontrolled; thus, whether hyperimmune gamma globulin is of benefit in such settings awaits a well-controlled clinical trial (2). 近来有研究表明高效价CMV免疫球蛋白可减少先天性感染引起的后遗症，但该研究不是对照研究，高效价免疫球蛋白是否对先天性感染有效还需随机对照临床研究来进一步验证（2）。 ADJUNCTIVE THERAPY Guided Medline Search 辅助治疗 The major adjunctive therapies that have been studied for the treatment and prevention of CMV disease are IVIG and CMVIG. As noted earlier, the combination of IVIG with ganciclovir in a number of studies seems to modestly improve outcome in the treatment of bone marrow transplant recipients and CMV pneumonia. Snydman and colleagues have championed the use of CMVIG to prevent/ ameliorate CMV disease in solid transplant recipients (174). 已经研究过的治疗和预防CMV感染的主要辅助治疗为IVIG和CMV免疫球蛋白。如前所述，有研究表明IVIG联合更昔洛韦治疗骨髓移植并发CMV肺炎较单药治疗可进一步改善预后。Snydman等人提出应用CMV免疫球蛋白预防或治疗实质脏器移植患者并发CMV感染有效（174）。 The use of CMVIG given in conjunction with ganciclovir has been evaluated in patients following cardiothoracic transplantation (198). In the study by Valantine et al. patients following heart, heart-lung or lung transplant were given ganciclovir plus CMVIG and compared to matched historical controls. At 3 years, there was a significant decrease in CMV disease (76% versus 39%), the proportion of rejection free patients (34% versus 11%) and overall survival (91% versus 63%) for the ganciclovir plus CMVIG group versus ganciclovir matched controls, respectively. Fewer cardiothoracic recipients also experienced obliterative bronchiolitis, 86% in the ganciclovir plus CMVIG versus 59% for those receiving ganciclovir only. The major problem with these data is the use of historical controls as the comparison group and the potential that other factors may have significantly impacted on disease outcome. Thus, the impact of CMVIG on heart, heart-lung, and lung transplant patients initiated early after transplantation requires a randomized controlled trial before definitive recommendations can be made. Valantine等对CMV免疫球蛋白联合更昔洛韦预防心肺移植患者CMV感染的作用进行了评估（198）。心脏、心肺或肺移植术后预防性应用更昔洛韦和CMV免疫球蛋白治疗组，与相匹配的对照组(未预防用药的既往移植患者)相比，术后3年CMV感染的发生率明显降低，分别为39%、76%，排异反应的发生率分别为11%、34%。与相匹配的单用更昔洛韦的对照组相比，存活率明显提高，分别为91%、63%，但闭塞性细支气管炎发生率也明显升高，分别为86%、59%。该研究主要缺点是应用历史病例作为对照，使许多影响预后的因素不能完全匹配。因此，在心脏、心肺或肺移植术后及早应用CMV免疫球蛋白是否能够改善患者预后还需要随机对照研究进一步证实。 The use of CMVIG for persons with HIV/AIDS has generally been unsuccessful. CMVIG was found to be unsuccessful in the prevention of CMV disease. Additionally, CMVIG when given in conjunction with ganciclovir for the treatment of CMV retinitis failed to prolong the time to retinitis progression in persons with advance AIDS prior to the availability of HAART. 许多研究发现HIV/AIDS患者应用CMV免疫球蛋白不能获益。CMV免疫球蛋白不能预防CMV感染，而且在HAART出现前CMV免疫球蛋白联合更昔洛韦治疗不能较更昔洛韦进一步延长AIDS患者CMV视网膜炎的无进展期。 As noted earlier, the use of CMVIG to prevent congenital infection is controversial and awaits controlled clinical trials before its use during pregnancy can be recommended. CMV免疫球蛋白预防先天性感染的有效性目前也有争议，推荐孕妇应用以前还需随机对照研究进一步评价其安全性及其疗效。 ENDPOINTS FOR MONITORING THERAPY Guided Medline Search 治疗的监测及终点 Ganciclovir Toxicity 更昔洛韦的毒副作用 Ganciclovir use requires monitoring the neutrophil count because neutropenia is the most important of the severe adverse reactions that limit the use of ganciclovir. Neutropenia or an absolute neutrophil count below l000/µL occurs in ~ 30% of patients receiving ganciclovir (60), but may occur in as many as 70% when administered with zidovudine (79). Severe neutropenia (< 500/µL) occurs in ~ 20% of patients. Neutropenia usually resolves with discontinuation of therapy and may be prevented by concomitant administration of granulocyte-or granulocyte macrophage colony-stimulating factor ( G-CSF or GM-CSF). Thrombocytopenia is a less common but potentially serious complication of ganciclovir, particularly in patients with AIDS, and further indicates its bone marrow suppressive effect. Other side effects of ganciclovir include rash, nausea, fever, vomiting, anemia, diarrhea, eosinophilia, confusion, seizures, and psychotic reactions in a small number of patients (24). 约30%应用更昔洛韦的患者会出现中性粒细胞减少或粒细胞绝对值小于1000/μL（60），当与齐多夫定合用时发生率为70%（79）。20%患者可引起严重粒细胞减少（小于500/μL），中性粒细胞减少是最常见的限制更昔洛韦使用的严重副作用，因此用药期间需监测中性粒细胞计数。停药后粒细胞通常可恢复正常，应用更昔洛韦同时使用G-CSF或GM-CSF可预防粒细胞减少。血小板减少不常见，是更昔洛韦较严重副作用，进一步说明其骨髓抑制毒性。少数患者会出现皮疹、恶心、发热、呕吐、贫血、腹泻、嗜酸性粒细胞增多、神智障碍、癫痫发作甚至精神症状（24）。 Foscarnet Toxicity 膦甲酸的毒副作用 The major toxicity of foscarnet is renal impairment, which occurs to some degree in most treated patients. Approximately 33% of 189 patients with AIDS and CMV retinitis who received intravenous foscarnet treatment developed impairment manifested as a serum creatinine concentration of 2 mg/dL or higher. Such elevations are usually, but not always, reversed on discontinuation of the drug. Because foscarnet chelates divalent cations, it has also been associated with serum electrolyte imbalance such as hypocalcaemia (15%), hypomagnesemia (50%), and hypokalemia (16%). Foscarnet has been associated with seizures in AIDS patients. Hypocalcemia may play a role in cases of unexplained seizures or arrhythmia. Anemia has been reported in 33% of patients receiving foscarnet. This has been manageable, and less than 1% required discontinuation of the drug for this reason. Granulocytopenia has been reported in 17% of patients, but only 1% was terminated from studies because of neutropenia. Penile ulceration may result from exposure of the glans penis to unchanged foscarnet in urine (5, 90). Patients receiving foscarnet must remain well hydrated in order to prevent such complications. 膦甲酸的主要副作用为肾毒性。189例AIDS合并CMV视网膜炎应用膦甲酸治疗过程中有33%出现肌酐大于2mg/dL等肾功能不全表现。停药后肾功能通常可恢复，但也有不可逆肾损害的报道。膦甲酸是一种二价离子螯合物，因此常引起电解质紊乱，如低钙血症、低镁血症、低钾血症。在AIDS患者中有引起癫痫发作的报道。33%的患者可出现贫血，但多不严重，仅有不到1%因贫血停药。17%的患者出现粒细胞减少，约1%因严重粒细胞减少需停药。膦甲酸部分经尿以原型排除，接触龟头可引起阴茎溃疡（5，90），用药时充分的水化可预防其发生。 VACCINES Guided Medline Search 疫苗 Although congenital infection with CMV remains the major infectious cause of birth defects in the developed world, there is still no vaccine available for protection against CMV. Considerable research is ongoing in this area; however, it is unlikely that a vaccine for CMV will be licensed and widely available within the next several years. 在发达国家，CMV先天性感染是新生儿缺陷最主要的感染性因素，但仍缺乏有效疫苗。目前正在进行大量的研究开发疫苗，但未来几年CMV疫苗被临床广泛使用的可能性不大。 PREVENTION Guided Medline Search Smart search 预防 Prophylactic/Pre-emptive Therapy Strategies 预防/抢先治疗策略 Bone Marrow Transplant Recipients 骨髓移植患者 Immunoglobulin: Although a number of early studies reported that use of immunoglobulin reduced CMV disease in marrow transplant recipients, other trials failed to demonstrate a benefit (16, 17, 103, 126, 135, 206). In a study of 97 seronegative marrow recipients, Bowden et al. (17) examined four assigned groups: (a) intravenous CMV immunoglobulin and seronegative blood products, (b) seronegative blood products alone, (c) CMV immunoglobulin alone, and (d) neither treatment. CMV infection in the four respective groups was 5, 13, 54, and 40%, respectively. The main conclusion of this study was that among 57 patients with seronegative donors, those who received seronegative blood products had significantly less infection (1 in 32) than those who received the standard blood products (8 of 25; P < .007). Immunoglobulin alone had no effect. This study showed that CMV infection and disease could be prevented in seronegative recipients who had seronegative donors by providing CMV-free blood products. The remaining question was whether immunoglobulin could prevent infection and disease in seronegative recipients with seropositive donors. Bowden et al. (16) showed in a randomized controlled study in 120 such patients that it could not. 人免疫球蛋白：早先有许多研究认为人免疫球蛋白可降低骨髓移植患者CMV感染发生率，但随后的许多试验并没有证实该观点（16，17，103，126，135，206）。在Bowden等人（17）的研究中，把97例CMV血清阴性的骨髓移植患者分为4组：1)CMV免疫球蛋白和血清阴性血制品治疗组2) 血清阴性血制品治疗组3) CMV免疫球蛋白治疗组4) 无治疗组。四组CMV感染的发生率分别为5%、13%、54%和40%。从该研究可看出，应用血清阴性血制品治疗与普通血制品相比CMV感染发生率明显降低，分别为1/32、8/25（P < .007），单纯应用人免疫球蛋白无效。因此，血清阴性骨髓移植患者可通过接受血清阴性供者骨髓和应用血清阴性血制品而预防CMV感染。当血清阴性移植患者接受CMV阳性供者骨髓时，人免疫球蛋白是否能预防CMV感染仍不明确，Bowden等（16）对120例此类患者进行的随机对照研究显示人免疫球蛋白无预防作用。 In a study of seropositive bone marrow recipients (195), among 308 seropositive recipients evaluated, 22% of control patients and 13% of immunoglobulin recipients developed interstitial pneumonia. The incidence of acute graft-versus-host disease (GVHD) was reduced from 51% in controls to 30% in immunoglobulin recipients. Whether the reduction of pneumonia was a direct effect of immunoglobulin or a secondary effect of the reduction of GVHD by immunoglobulin is unclear. These findings were not confirmed in a subsequent study (154). 对308例血清阳性骨髓移植患者研究显示，对照组和人免疫球蛋白治疗组间质性肺炎发生率分别为22%、13%，急性移植物抗宿主病发生率分别为51%、30%（195）。肺炎发生率的下降是人免疫球蛋白直接作用的结果还是通过降低GVHD而引起的继发性作用目前仍不明确。随后进行的许多研究与该研究的结果并不相符（154）。 In summary, there are currently no compelling data that demonstrate benefit of immune globulin or hyperimmune globulin for the prevention or amelioration of CMV disease following in bone marrow recipients and this treatment is not recommended in such settings. 总之，目前尚缺乏足够的证据表明人免疫球蛋白或高效价免疫球蛋白可预防或减少骨髓移植患者CMV感染的发生率，因此不推荐骨髓移植患者预防性的使用免疫球蛋白。 Antiviral Agents: Patients who are CMV seropositive before marrow transplantation are at greater risk for developing CMV disease after transplantation than seronegative recipients. Regardless of the donor serologic status, the frequency of infection in the first 100 days after transplantation is about 70% (124). This group of patients has been primarily targeted for testing antiviral prophylaxis and therapy. 抗病毒药物：接受移植前CMV血清阳性的患者移植后发生CMV感染的风险更高，不管供者CMV血清学状态，移植后100内CMV感染的发生率约为70%（124）。预防治疗应首先试用于此类患者。 Meyers et al. (125) found that intravenous acyclovir (500 mg/m2 given every 8 h starting 5 days before transplantation of CMV seropositive subjects and continued until day 30 thereafter) reduced the incidence of CMV disease from 38% to 22% and the incidence of CMV infection from 75% to 59%. Transplantation-associated mortality was reduced from 54% to 29%. The European Acyclovir Study Group (147) evaluated intravenous acyclovir at a dose of 500 mg/m2 thrice daily or oral acyclovir for the first 30 days after transplantation and then oral acyclovir or placebo until day 210. The rate of CMV infection, frequency of viremia, and mortality were lower in the group that received intravenous acyclovir. However, the frequency of CMV disease was similar in the two groups. Boeckh et al. (13) evaluated intravenous acyclovir from 5 days before autologous transplantation to day 100 in a retrospective study. There was no difference in the incidence of CMV disease or pneumonia. Thus, although some studies have established a benefit of acyclovir (including valacyclovir) for prevention of CMV disease, its benefits are inferior to ganciclovir or foscarnet and its use is not recommended for prevention of CMV disease. Meyers等人（125）发现静脉用阿昔洛韦（500mg/M2，每8小时一次，移植前5天至移植后30天）可使CMV疾病发生率由38%降至22%，使CMV感染发生率了由75%降至59%。移植相关死亡率由54%降至29%。欧洲阿昔洛韦研究组研究发现（147），在骨髓移植后前30天内应用静脉阿昔洛韦（500mg/m2，每日3次），后口服阿昔洛韦维持至移植后210天，与相同疗程的单纯口服阿昔洛韦相比，CMV感染、病毒血症发生率及病死率均有所降低，但CMV疾病发生率无明显差异。Boeckh等（13）对自体移植患者进行的回顾性研究显示，移植前5天至移植后100天静脉应用阿昔洛韦并不能降低CMV疾病及肺炎的发生率。尽管仍有部分研究认为阿昔洛韦（包括伐昔洛韦）预防CMV感染有一定疗效，但明显差于更昔洛韦或膦甲酸，因此并不推荐用于CMV感染的预防治疗。 There are two approaches to the use of ganciclovir in CMV seropositive marrow recipients. The first is early treatment or pre-emptive therapy where patients identified as having active CMV infection historically by surveillance cultures or currently usually by direct CMV antigen or PCR detection in blood are then given ganciclovir. The second approach is to administer ganciclovir after engraftment to all seropositive patients. CMV血清阳性骨髓移植患者何时应用更昔洛韦治疗目前有两种观点：一是早期治疗或抢先治疗，即当CMV培养、抗原检查或PCR检测确定患者有活动性CMV感染时再应用更昔洛韦；第二种观点是所有血清阳性患者均应用更昔洛韦预防性治疗。 Following the first approach, Schmidt et al. (160) performed bronchoalveolar lavage (BAL) surveillance cultures at the median day of engraftment (day 22) and enrolled those with CMV-positive cultures. Twenty patients were randomized to the placebo group and 20 to the treatment group, who received ganciclovir from day 35 after transplantation to day 120. CMV pneumonia was reduced from 70% to 25%. Of the 55 patients who were not positive by BAL (and thus not eligible for the study), 22% developed CMV pneumonia. Goodrich et al. (70) selected patients for prophylaxis by screening for positive CMV cultures from blood, throat washes, or urine. Patients received either ganciclovir until day 100 after transplantation or placebo. Results were obtained on 102 patients. CMV disease was reduced from 43% (15 of 35) in the placebo group to 3% (1 of 37 patients) in the treatment group during the first 100 days after transplantation. 有学者针对第一种观点进行了研究，Schmidt等（160）在患者移植后（平均约22天）取支气管肺泡灌洗液作病毒培养，把培养阳性者随机分入两组，安慰剂组和更昔洛韦治疗组（疗程为从移植后35天至120天）CMV肺炎发生率分别为70%、25%。55例支气管肺泡灌洗阴性的患者，有22%发生CMV肺炎。在Goodrich等（70）的研究中，把102例CMV血培养、含漱液培养或尿培养阳性的骨髓移植患者随机分为安慰剂组和治疗组（移植后开始更昔洛韦治疗至移植后100天），在移植后100内CMV疾病发生率分别为43%（15/35）、3%（1/37）。 Following the second approach, Goodrich et al. (69) gave ganciclovir to all 33 patients, from engraftment to 100 days after transplantation; 45% of the placebo recipients (14 of 31) developed CMV infection 100 days after transplantation compared with 1 (3%) ganciclovir recipient. Neutropenia occurred in 30% of the ganciclovir recipients. Mortality did not differ between the two groups. Winston et al. (205) gave ganciclovir for 1 week before marrow infusion and then starting after engraftment until day 100 after transplantation. CMV infection was reduced from 56% to 24%. 针对第二种观点的研究也有许多。Goodrich等（69）对33例骨髓移植患者进行了预防治疗（在移植后给予更昔洛韦至移植后100天），与安慰剂组相比CMV感染发生率明显降低，分别为3%（1/33）、45%（14/31）。更昔洛韦治疗组30%出现粒细胞减少。两组病死率并无明显差异。Winston等（205）进行的对照研究显示，更昔洛韦预防治疗（骨髓移植前1周至移植后100天）可使CMV感染发生率由56%降至24%。 The studies cited above show that ganciclovir is effective in reducing CMV disease if administered ( a) routinely to all patients or (b) selectively to those found to be positive by surveillance cultures. But if one avoids excess toxicity by restricting administration to patients at higher risk, there is the danger of missing those who become ill without positive surveillance cultures. At the moment there is no perfect solution to this problem. However, studies using antigenemia or quantitative PCR provide excellent although not perfect surveillance. 上述研究显示，不管是所有骨髓移植患者还是病毒培养阳性的患者应用更昔洛韦均可有效预防CMV感染。但如果为了避免药物毒性未予病毒培养阴性的高危患者预防治疗，有可能遗漏那些将来发生CMV感染的病例。针对这一矛盾尚无完美的解决办法。目前所采用的病毒抗原血症或PCR定量检测，尽管还不完善，但可对病情进行非常有效的监测。 Prevention of CMV in Organ Transplant Recipients 器官移植患者CMV感染的预防 Prevention of CMV in transplant recipients using antiviral agents is generally approached using one of two strategies: 1), preemptive therapy where the antiviral agent is targeted towards patients with early viral replication or viremia in an attempt to prevent the progression of asymptomatic infection to CMV disease, and 2), prophylaxis where the drug is administered to all patients for the period that they are deemed to be at risk for CMV, usually 90-100 days post-transplant (165, 141). Major advantages of the prophylactic approach include the fact that it obviates the need for frequent monitoring to detect early viral replication, is reliably protective against CMV during the time that the antiviral agent is employed, and likely provides protection against indirect sequelae or secondary outcomes associated with CMV. Disadvantages of this approach are that most patients while accruing the cost and possibly the risk of toxicity associated with antiviral agent, are unlikely to benefit from it. There is also a potential concern for the emergence of antiviral resistance. Additionally, accumulating data show that while CMV disease can be effectively prevented during the time that antiviral prophylaxis is employed (first 3 post-transplant months), a significant proportion of the patients, particularly in the recipient seronegative/donor seropositive (R-/D+) group, develop CMV disease upon discontinuation of prophylaxis (1, 93, 109, 140). Late-onset CMV disease, defined as CMV disease occurring after 100 days post-transplant, has emerged as a significant complication with the use of valganciclovir prophylaxis in the current era (1, 93, 109, 140, 165) . 器官移植患者预防CMV感染通常采用下列两种措施之一：1）抢先治疗：当患者处于病毒复制或病毒血症早期时，为防止无症状性CMV感染进展，进行抗病毒治疗；2）预防治疗：处于CMV感染危险期的所有患者均应用抗病毒治疗，高危期通常在移植后90-100天内（165，141）。预防治疗可有效防止CMV感染及其所引起的后遗症或并发症，而且可避免频繁监测CMV病毒学指标。但是抗病毒药物的费用及毒副作用是预防治疗的主要缺陷。预防治疗也有可能诱导病毒耐药的产生。而且有资料表明，尽管在预防治疗期间可避免CMV感染，但有部分患者尤其是受者血清阴性/供者血清阳性（R-/D+）移植患者在停止预防治疗后出现了CMV感染（1，93，109，140）。后期CMV感染（发生于移植100天以后）是目前缬更昔洛韦预防治疗的重要并发症（1，93，109，140，165）。 Advantages of the preemptive therapy approach are that the antiviral agent is directed only towards patients at high-risk for CMV disease, and therapy is employed for a defined and shorter duration. This strategy, including the costs of surveillance monitoring is associated with lower overall costs. Existing data have not documented late-onset CMV disease with valganciclovir used as preemptive therapy (39, 119, 167). The proposed basis of this observation is that asymptomatic viremia implicit in preemptive therapy approach may facilitate CMV-specific immune responses that are critical in long-term protective immunity against the virus (167). 抢先治疗主要针对CMV感染的高危人群，治疗疗程较短，治疗费用也不高。目前还没有应用缬更昔洛韦抢先治疗后发生后期CMV感染的报道（39，119，167）。抢先治疗可使无症状CMV病毒血症患者更容易产生针对CMV特异的免疫反应，进而获得长期免疫力，避免后期CMV感染的出现（167）。 Antiviral agents for prophylaxis: Options for antiviral agents that can be employed as prophylaxis include acyclovir, valacyclovir, or ganciclovir derivatives. Acyclovir due to its poor in vitro activity against CMV and low oral bioavailability, has not proven particularly effective for the prevention of CMV disease. Comparative studies have shown lower efficacy rates for acyclovir compared to ganciclovir containing regimens (208). Valacyclovir is a valyl ester of acyclovir with improved oral bioavailability. In a placebo controlled trial in renal transplant recipients, valacyclovir (2 g orally four times daily) significantly reduced the incidence of CMV disease and that of acute allograft rejection (112). Although not as effective as ganciclovir, valacyclovir represents a cost-effective alternative to ganciclovir in renal transplant recipients. 预防治疗的抗病毒药物：阿昔洛韦、伐昔洛韦或更昔洛韦衍生物可作为预防用药。阿昔洛韦体外抗CMV活性弱且口服生物利用度低，对CMV感染预防作用较差。有对比研究显示与更昔洛韦相比，阿昔洛韦有效率更低（208）。伐昔洛韦是阿昔洛韦的缬氨酰酯，生物利用度高。与安慰剂进行的对照研究显示，肾移植患者应用伐昔洛韦（2g口服每日四次）可有效降低CMV感染的发生率和同种异体移植物排斥反应（112）。尽管疗效不如更昔洛韦，但伐昔洛韦经济有效，可作为肾移植患者的备选用药。 Intravenous ganciclovir employed for a prolonged period has proven effective for CMV disease. In a randomized trial that involved predominantly seropositive patients, prophylaxis with intravenous ganciclovir that was administered to liver transplant recipients for 100 days was associated with a CMV disease rate of 1% in all patients, and 10% in those at risk for primary CMV infection, i.e., seronegative recipients of seropositive allografts (208). However, this approach did not gain wide acceptance because of the requirement of prolonged vascular access for intravenous administration of the drug. 有研究表明长期静脉使用更昔洛韦可降低CMV感染的发生率。在对一组肝脏移植患者（大部分患者CMV血清阳性）进行的随机对照研究显示，移植后静脉应用更昔洛韦100天CMV感染发生率为1%，其中原发CMV感染的高危患者（即R-/D+患者）为10％（208）。但由于该治疗方法需长期留置静脉通路及静脉用药，并没有得到广泛的应用。 Administration of oral ganciclovir for 100 days after liver transplantation reduced the rate of CMV disease to 5% among all patients, and to 15% among those at risk for primary CMV infection (64). However, given the poor oral bioavailability of oral ganciclovir, a potential concern in the setting of prolonged use of this agent is suboptimal suppression of the virus and the emergence of ganciclovir-resistant CMV. Patients at particular risk are those receiving intense immunosuppression and the R-/D+ group. At one institution that employed prolonged prophylaxis with oral ganciclovir, 10% of the patients who underwent solid organ transplantation developed CMV disease within the first year after transplantation (111). Of note, 20% of the patients with CMV disease had ganciclovir-resistant CMV (111). In another report, 11 infections with ganciclovir-resistant CMV in organ transplant recipients were documented, a majority of these patients had received prolonged oral ganciclovir prophylaxis (87). 肝脏移植后口服更昔洛韦100天可使CMV感染发生率降至5％，其中原发性感染的高危患者降至15％（64）。然而，由于口服更昔洛韦生物利用度较差，延长用药时间并不利于充分抗病毒，而且容易产生更昔洛韦耐药的CMV。接受强化免疫抑制治疗或R-/D+的患者是CMV感染的高危人群。有临床机构采用延长口服更昔洛韦预防治疗时间的方法，10%的患者器官移植后第一年内发生了CMV感染（111），其中更昔洛韦耐药率占20%（111）。有文献报道了11例器官移植后发生更昔洛韦耐药CMV感染的患者，其中绝大部分接受过口服更昔洛韦长期预防治疗（87）。 Valganciclovir is a valine ester prodrug of ganciclovir. Following ingestion, a vast majority of valganciclovir, prior to reaching system circulation, is hydrolyzed to ganciclovir (143). The oral bioavailability of valganciclovir is such that ganciclovir levels achievable are comparable to those attained with intravenous ganciclovir (143). In a randomized trial comparing valganciclovir 900 mg once daily with oral ganciclovir 1000 mg tid administered for 100 days as prophylaxis in CMV recipient negative/donor positive organ transplant recipients, neither group experienced CMV disease during the treatment phase (140). By 12 months, however, the incidence of CMV disease in the valganciclovir and oral ganciclovir groups was 17.2% and 18.4%, respectively (140). 缬更昔洛韦是更昔洛韦的前体药物，口服吸收后绝大部分水解为更昔洛韦进入血液循环发挥作用（143）。缬更昔洛韦生物利用度很高，口服后更昔洛韦血药浓度不亚于静脉注射更昔洛韦（143）。有学者对R-/D+器官移植患者进行了的随机对照研究，分别应用缬更昔洛韦（900mg每日一次口服）和更昔洛韦（1000mg每日3次口服）预防治疗，疗程为100天，研究发现治疗期间两组均未出现CMV感染病例（140），但在移植12个月后，缬更昔洛韦组和更昔洛韦组CMV感染发生率分别为17.2%、18.4%（140）。 Approach to prophylaxis: Options for antiviral agents as prophylaxis include valganciclovir (900 mg qd), oral ganciclovir (1 g tid), or intravenous ganciclovir (5 mg/kg/d). Breakthrough CMV disease is a rare occurrence during the use of either of these agents. However, late-onset CMV disease may occur in 2.5 - 17% of the patients receiving oral ganciclovir, and 5.5 - 18% of those receiving valganciclovir (1, 10, 93, 110, 140, 166) . Valacyclovir (8 g/d) is an alternative in renal transplant recipients, particularly in the R+ subgroup. It should however be noted that 57% of all episodes of CMV disease in patients receiving valacyclovir were also late occurring. Based on a higher incidence of tissue invasive disease with valganciclovir compared to oral ganciclovir in liver transplant recipients in the PV-16000 trial, the FDA has cautioned against the use of valganciclovir in liver transplant recipients. In the clinical setting, however, valganciclovir has been used in liver transplant recipients (10, 93, 109, 167). 预防治疗：预防性抗病毒治疗可选用缬更昔洛韦（900mg/日）、口服更昔洛韦（1g，3次/日）或静脉更昔洛韦（5mg/kg/日）。用药期间很少出现CMV感染，但停药后仍有一部分患者会发生CMV感染，分别约为应用口服更昔洛韦或缬更昔洛韦患者的2.5-17%、5.5-18%（1，10，93，110，140，166）。伐昔洛韦（8g/日）可作为肾移植患者（尤其是在R+阳性时）预防治疗的备选用药，但仍有57%的病例在晚期发生了CMV感染。PV-16000研究显示，肝移植患者应用缬更昔洛韦预防治疗与口服更昔洛韦相比，侵袭性CMV感染的发生率更高，因此FDA不推荐肝脏移植患者应用缬更昔洛韦预防治疗。然而临床上缬更昔洛韦用于肝移植患者仍很常见的（10，93，09，167）。 Valganciclovir and intravenous ganciclovir are rational choices for antiviral prophylaxis in lung transplant patients. Lung transplant recipients are at high-risk for the development of ganciclovir resistant CMV (108). Resistant virus has been documented in 1 - 4.4% of the R+, and 9-27% of the R-/D+ lung transplant recipients (108). Given that most such cases have occurred after prolonged exposure to oral ganciclovir, this agent is a less desirable option, for CMV prophylaxis in lung transplant recipients, particularly in the R-/D+ subgroup. 缬更昔洛韦和静脉更昔洛韦是肺移植患者预防性抗病毒治疗的首选药物。由于肺移植患者容易产生更昔洛韦耐药（108），据报道，在R+患者中约为1-4.4%，R-/D+患者中为9-27%（108），其中大部分耐药病例都是应用口服更昔洛韦长期预防治疗的患者，因此口服更昔洛韦不适于肺移植尤其是R-/D+患者的预防治疗。(R+表示器官接受者CMV血清阳性，R-/D+表示器官接受者CMV血清阴性但供者CMV血清学阳性) The usual duration of antiviral prophylaxis is 90-100 days post-transplant. It has been proposed that in lung transplant recipients 180 compared to 100 days may be a more optimal duration of prophylaxis (216). Freedom from CMV infection and disease was greater in patients receiving 180 days (90%) compared to those receiving 100-170 days (64%) or < 100 days (59%) of prophylaxis (216). 预防治疗的通常疗程为移植后90-100天。有研究认为肺移植预防治疗的疗程为180天要优于100天（216）。疗程为180天与100-170天、100天相比，无CMV感染患者比例最高，分别为90%、64%、59%（216）。 Antiviral agents for preemptive therapy: The success of preemptive therapy hinges upon early and reliable detection of CMV viremia. Existing studies in organ transplant recipients have employed either CMV antigenemia or a CMV DNA based molecular assays to initiate preemptive therapy. The predictive value of various diagnostic assays for the early detection of CMV disease is outlined in Table 5. CMV antigenemia is easy to perform, has a rapid turn-around time, and can be quantitated. Although, CMV disease may precede detectable antigenemia, most studies in transplant recipients have validated antigenemia as a reliable tool for initiating preemptive therapy (167, 200). Potential disadvantages of the antigenemia test include the need for immediate processing of specimens and the requirement of a leukocyte count of ≥ 200 cells/ mm. 抢先治疗的抗病毒药物：抢先治疗的关键是能够早期准确的发现CMV病毒血症。已有研究采用CMV抗原血症或CMV DNA分子测定作为启动抢先治疗的指标。各种检测手段对早期CMV感染预测价值的描述（详见表5）。CMV抗原血症检测简单、迅速，及时、可定量。尽管CMV疾病可出现于抗原血症之前，但大部分研究仍把抗原血症作为启动抢先治疗的可靠指标（167，200）。抗原血症检测也有不足之处，血标本不能保存需立即处理，血液中白细胞需大于200个/mm3，否则准确性降低。 Nucleic acid based assays obviate the need for immediate processing of the samples. CMV-DNA detection by PCR in the leukocytes may be overly sensitive and does not reliable distinguish latent CMV infection from replicating CMV infection. Detection of CMV DNA by means of PCR of plasma, whole blood hybrid capture assay or CMV RNA (mRNA) is considered specific for replicating virus (71). A quantitative PCR that predicts CMV disease and could be used in a preemptive strategy has not been reliably defined. In one report, quantitative PCR in the range of 2000 - 5000 copies/ml was deemed to be the optimal cut-off for predicting CMV disease with a positive and negative predictive value of 50% and 96.6%, respectively (86). At present, preemptive therapy for transplant recipients may be based on results of the antigenemia test or quantitative PCR, depending on the access to the test. 核苷酸序列检测不需立即处理血标本，但PCR方法检测CMV DNA过分敏感，区分潜伏性CMV感染和活动性CMV感染可靠性较差。血浆CMV DNA PCR检测、全血杂交捕捉试验或CMV RNA（mRNA）检测是判断病毒复制较特异的方法（71）。PCR定量检测是可用于CMV疾病的预测，可作为启动强效治疗的判断指标，但还需进一步研究确定其不同值得临床意义。有学者认为PCR定量检测值在2000-5000拷贝/ml预测CMV疾病最佳，阳性预测值和阴性预测值分别为50%、96.6%（86）。目前，可根据情况选择抗原血症检测或PCR定量检测作为移植患者抢先治疗的判断指标。 Approach to preemptive therapy: The underlying principle and the intent of preemptive therapy are to prevent the progression of asymptomatic viremia detectable by a sensitive assay, to CMV disease. Thus, CMV infection (viremia) would already have occurred prior to the initiation of antiviral therapy. Ideally, therefore, the antiviral agent employed should be able to completely suppress the replicating virus. Acyclovir or its prodrug valacyclovir, given their poor activity against CMV are largely unsuitable agents for preemptive therapy. Use of intravenous ganciclovir, while effective as preemptive therapy, is impractical and inconvenient because of the requirement of intravenous access. Preemptively administered oral ganciclovir at dosages ≥3 gm/day has also been shown to be effective in reducing the risk of CMV disease (142, 167, 196). In liver transplant recipients, preemptive oral ganciclovir was associated with a significantly lower risk of CMV disease (RR 0.11, 95% CI, 0.01 - 0.96, p = 0.04) compared to the control group that did not receive prophylaxis (196). Oral ganciclovir for 6 weeks initiated upon detectable CMV antigenemia was also effective in preventing CMV disease in liver transplant recipients in another report (167). Oral ganciclovir, however, may not be an optimal antiviral agent for preemptive therapy. Given its poor bioavailability and low achievable serum levels, oral ganciclovir may not only be suboptimal as preemptive therapy in the setting of high viral load, but may predispose to the emergence of ganciclovir resistance. CMV replication dynamics in liver transplant recipients have shown that viral growth in CMV-experienced host will be substantially inhibited by oral ganciclovir at a dose of 1 gm orally tid (55). In CMV naïve host however, in whom an anti-CMV agent must have an efficacy of ≥ 93% in inhibiting viral replication, oral ganciclovir may not be optimal (55). During preemptive therapy with oral ganciclovir in liver transplant recipients the maximum viral load attained was lower, but not significantly different compared to placebo (mean, 734 vs. 2603 copies/106 peripheral blood leukocytes, respectively, p = .19) (150). Two of 6 patients, both R-/D+, with persistent viral replication on oral ganciclovir subsequently developed CMV syndrome (150). 抢先治疗：抢先治疗的目标是预防无症状性病毒血症进展为CMV疾病。在抗病毒治疗时可能已经存在病毒复制，因此，理想情况下，抗病毒药物应能够完全抑制病毒复制。阿昔洛韦或其前体药物伐昔洛韦由于抗CMV活性弱，不适用于抢先治疗。尽管静脉更昔洛韦有效，但因需留置静脉通路，应用不方便，临床上并不实用。口服更昔洛韦（至少3g/日）也可降低CMV疾病的风险。肝移植患者中，口服更昔洛韦抢先治疗组与不治疗的对照组相比CMV疾病风险明显降低（RR 0.11，95%CI：0.01-0.96；P=0.04）。另一研究也获得类似的结论，CMV病原血症阳性的肝脏移植患者应用口服更昔洛韦治疗6周可有效预防CMV疾病（167）。但由于口服更昔洛韦生物利用度低，可达到的血药浓度有限，容易使病毒对更昔洛韦耐药，因此口服更昔洛韦不是抢险治疗最理想的药物，尤其是当病毒载量很高时。肝脏移植患者体内CMV复制动力学显示，移植前曾患有CMV感染的患者应用口服更昔洛韦（1g，3次/日）可几乎完全抑制病毒的活性（55）。口服更昔洛韦抢先治疗肝脏移植患者可使病毒载量的极量略有下降，但与安慰剂相比并没有显著差异，分别为734、2603拷贝/106外周血白细胞（0.19）（150）。在口服更昔洛韦预防治疗的6例患者中，有2例仍有CMV持续复制，并随后出现CMV感染，这两例均为R-/D+（150）。 Although the FDA has cautioned against the use of valganciclovir in liver transplant recipients, this agent has been shown to be effective as preemptive therapy in organ transplant recipients, including those undergoing liver transplantation. Of 59 liver transplant recipients, including R-/D+ patients, 28.8% (17/59) received valganciclovir as preemptive therapy for CMV infection (antigenemia) (167). At a median follow-up of 3.1 person years, there were no episodes of CMV disease. Another report in solid organ transplant recipients compared the efficacy of preemptive therapy with valganciclovir employed as preemptive therapy with intravenous ganciclovir (119). There were no episodes of CMV disease or of late-onset CMV disease in either group at 12-month follow-up (119). Of 301 high-risk seropositive transplant recipients who received preemptive therapy with valganciclovir for CMV antigenemia, none had CMV disease when followed for a median of 14 months (40). 尽管FDA建议缬更昔洛韦应谨慎用于肝脏移植患者，但研究显示该药用于器官移植包括肝移植患者抢先治疗有效。在59例包括R-/D+的肝移植患者中，28.8%（17/59）接受缬更昔洛韦用于CMV感染（CMV病原血症阳性）的抢先治疗，平均随诊3.1年，无1例发生CMV疾病（167）。 有研究对比缬更昔洛韦与静脉更昔洛韦疗效发现，接受抢先治疗的器官移植患者，不管应用那种药物，随诊12个月，无1例CMV疾病或后期CMV疾病发生（119）。有研究报道，对301例R+且病原血症阳性的器官移植患者应用缬更昔洛韦抢先治疗，平均随诊14个月，均无CMV疾病的出现（40）。 The goal should be to reach an undetectable level of viremia by either antigenemia or PCR, whichever test prompted the initiation of preemptive therapy. The duration of preemptive therapy has typically ranged from 14-21 days. Antigenemia level with preemptive valganciclovir decreased by 99.5% at 2 weeks compared to baseline (167). In another study, the time to become PCR negative with preemptive valganciclovir was 15.5 days, the baseline CMV viral load being 3.8 log10 genomes/mL (119). 提高检测方法的敏感性，及早发现病毒血症，以便能够尽快给予抢先治疗。抢先治疗的常规疗程为14-21天。缬更昔洛韦抢先治疗2周可使血中抗原水平降低99.5％（167），另有研究显示应用缬更昔洛韦约15.5天可使PCR病毒检测转阴（119）。 Organ transplant recipients receiving monoclonal or polyclonal antilymphocytic antibodies are at high-risk for CMV infection. These patients should receive a potent antiviral agent such as intravenous ganciclovir or valganciclovir initiated in conjunction with the antilymphocytic agent and continued for ~ 2 weeks. This form of CMV prevention triggered by a clinical event is termed targeted or selective prophylaxis. 应用单克隆或多克隆抗淋巴细胞抗体的器官移植患者是CMV感染的高危人群。因此，此类患者在接受抗淋巴细胞药物同时，应预防应用抗病毒药物如缬更昔洛韦或静脉用更昔洛韦2周。这种针对某一特殊临床情况的CMV预防称为靶向预防或选择性预防。 Prophylaxis in HIV Patients HIV患者的预防治疗 The most common and most debilitating form of CMV disease is CMV retinitis, which may eventually lead to blindness despite effective antiviral therapy if antiretroviral therapy is unable to raise the CD4+ lymphocyte count above 100-150 cells/µL. In the pre-HAART era, in a placebo-controlled study, Spector et al. (Roche 1654 study, 188) randomized (in a 2:1 ratio) 486 patients who received 1000 mg oral ganciclovir three times daily and 239 controls. Entry criteria were a CD4+ count of 50/µL or less or l00/µL or less and a history of an AIDS-defining event. The incidence of CMV retinitis after 18 months of observation was 39% in the placebo group and 18% in the treated group. Total CMV disease was significantly reduced by treatment (39% vs. 20%), including investigator-reported colitis (13% vs. 4%). Although there was a trend toward overall survival benefit for patients treated with oral ganciclovir (relative risk = 0.8), the difference was not statistically significant (P = 0.14). Patients in the treated group had more instances of neutropenia, were more frequently on granulocyte colony-stimulating factor, and had more frequent elevations of serum creatinine. 最常见和最易致残的CMV疾病是CMV视网膜炎，如果抗逆转录病毒治疗不能使CD4+淋巴细胞升至100-150个/μL以上，即使经过有效的抗病毒治疗，也有可能导致患者失明。在HAART出现前，Spector等（188）进行了随机对照研究，评价更昔洛韦在AIDS患者中预防CMV感染的作用。该研究入选标准为CD4+淋巴细胞≤50个/μL或CD4+淋巴细胞≤100个/μL且有AIDS期病史。486例AIDS患者被随机（按2：1分配）分入治疗组（更昔洛韦1000mg口服，每日3次），239例患者分入安慰剂组。随诊18个月，结果显示治疗组和安慰剂组CMV视网膜炎的发生率分别为18%、39%。治疗组CMV疾病（包括研究者报告的结肠炎）发生率有明显降低（20%VS39%）。尽管应用口服更昔洛韦有改善存活率的倾向，但两组存活率并无统计学差异（P=0.14）。治疗组中性粒细胞减少发生率更高，需G-CSF治疗的可能性更大，血肌酐升高更常见。 In a second study performed by the CPCRA, oral ganciclovir prophylaxis in persons with AIDS failed to demonstrate a benefit in decreasing CMV disease (22). However, several important differences existed between the two studies with the most important being the monitoring of retinitis in both studies. Whereas the earlier study by Spector and colleagues screened participants at baseline and every two months with a dilated eye examination performed by an experienced ophthalmologist, the second study did not have dilated eye examinations at their clinical site unless the study participant complained of visual disturbances. Although a trend in favor of ganciclovir was observed in the CPCRA study, the difference was not statistically significant. Of interest, however, in this additional study a trend toward improved survival was also observed in the ganciclovir treated group (relative risk = 0.84; P= 0.1). 但在CPCRA随后进行的研究中，并未发现更昔洛韦具有预防AIDS患者CMV感染的作用（22）。但两个研究在视网膜炎的监测方面有明显的不同。Spector等进行的研究中，受试者在研究开始及研究期间的每两个月由经验丰富的眼科医生为其进行眼科检查。CPCRA进行的研究中，仅当受试者有眼部症状时才进行眼科检查。尽管CPCRA的研究表明更昔洛韦似乎有一定的预防作用，但研究数据并没有统计学意义。有趣的是，该研究发现更昔洛韦可能改善存活率（相对危险度=0.84；P=0.1）。 Spector et al further examined the impact of viral load as determined by CMV DNA PCR of plasma in 1654 study participants. The development of CMV disease was directly correlated with the quantity of CMV DNA present at study entry. Importantly, however, for study participants randomized to receive ganciclovir, those who went from plasma PCR positive to negative developed significantly less CMV disease than those who remained PCR positive (20% versus 48%, respectively; relative risk 0.33, P< 0.001). Of note, overall survival was also predicted by the presence and quantity of CMV DNA in plasma. Moreover, study participants randomized to receive ganciclovir who went from CMV DNA positive to negative had significantly improved survival compared to those who remained PCR positive (24% versus 47%, relative risk, 0.36, P< 0.001). Spector等为评价病毒载量对CMV感染的影响，对1654例受试者血浆进行了CMV DNA PCR检测。研究发现CMV感染的发生直接与纳入研究时CMV DNA病毒载量相关。随机纳入治疗组的受试者中，治疗后CMV PCR转阴的患者，与持续阳性者相比CMV感染发生率更低（分别为20%、48%，相对危险度0.33，P<0.001）。研究还发现，患者生存率与CMV DNA是否阳性以及病毒载量相关。而且治疗组中CMV DNA转阴的患者较持续阳性者生存率明显改善（分别为47%、24%，相对危险度0.36，P<0.001）。 In total, in the current recommendation of The U. S. Public Health Service/Infectious Diseases Society of America Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus states, Prophylaxis with oral ganciclovir may be considered for HIV-infected adults and adolescents who are CMV seropositive and who have a CD4+ T-lymphocyte count less that 50 cells/µL. Ganciclovir-induced neutropenia, anemia, conflicting reports of efficacy, lack of proven survival benefit, the risk for developing ganciclovir-resistant CMV, and cost are among the issues that should be considered when deciding whether to institute prophylaxis in individual patients (197) . It should be noted, however, that in the HAART era the development and course of CMV retinitis has been greatly altered and for patients with CMV DNA detected in their plasma, pre-emptive treatment may not be necessary for the patient who is initiated on HAART. 总而言之，目前美国公共卫生服务机构/感染病学会关于预防HIV患者机会性感染的指南建议，当HIV感染者CMV血清阳性和CD4+淋巴细胞小于50个/μL时，可考虑口服应用更昔洛韦预防治疗。但有研究也认为更昔洛韦无预防作用，而且目前仍缺乏更昔洛韦改善生存率的证据,每位患者开始预防治疗之前均应充分考虑以下因素：更昔洛韦的毒副作用如中性粒细胞减少、贫血，诱导更昔洛韦耐药CMV产生的风险，费用的增加等（197）。然而随着HAART广泛应用，CMV视网膜炎的发病及病程特点已经发生了显著的变化，抢先治疗的地位也明显降低了。 INFECTION CONTROL 传染的预防 No special precautions are necessary for hospitalized patients known to be actively infected with CMV. Patients do not require isolation or single rooms. It is important, however, that individuals adhere to strict handwashing after exposure to bodily secretions including saliva, urine and tears because infectious CMV can be present such fluids. Additionally, seronegative immunocompromised patients and uninfected preterm infants should be administered CMV seronegative blood and blood products to prevent transmission from donor to recipient. Universal precautions in handling blood, blood products and secretions are recommended in all patient care settings and are sufficient for control of CMV. 活动性CMV感染的住院患者不需要隔离或单间等特殊管理。传染性CMV可经唾液、尿液、泪液等体液传播，因此所有接触患者体液的人员均应严格洗手。另外，免疫缺陷的血清阴性患者和无CMV感染的早产儿应避免输注血清阳性供者的血液或血制品，以防CMV的传播。医疗单位处理血液、血制品或分泌物需遵守一定的规范，这足以防止CMV的传播。 CONTROVERSIES 争议 A number of important controversies remain regarding the optimal approaches to the prevention and treatment of the broad range of CMV diseases observed in diverse patient populations. To a great extent, the different underlying clinical conditions that are associated with CMV diseases have complicated treatment approaches. Generally, the underlying risk factor for serious CMV infection is immunosuppression, particularly of cell-mediated immunity. However, clearly the immunosuppression associated with AIDS versus marrow or stem cell transplantation versus solid organ transplantation differs considerably and appears to have a major impact on the pathogenesis of CMV diseases in these settings. 关于如何最佳的预防和治疗不同患者的CMV感染尚存在很多争议。在一定程度上，患者病情的多样性使CMV感染的治疗更加复杂。通常情况下，免疫抑制状态尤其是细胞免疫缺陷是严重CMV感染的潜在危险因素。AIDS、骨髓移植、造血干细胞移植及器官移植患者的免疫抑制情况各有不同，不同疾病状态下的CMV感染的机制也有所区别。 In CMV seropositive patients with advanced AIDS (CD4+ lymphocyte counts below 50 cells/µL) and organ transplant recipients either receiving a seropositive transplant or previously CMV positive, the use of pre-emptive therapy versus universal prophylaxis remains controversial (168). Issues including efficacy, logistics, duration, cost and the relative risk of disease in a given population and the adequacy of treatment impact on decision making. In the HAART era, patients begun on effective antiretroviral therapy may not require pre-emptive treatment. If pre-emptive therapy is the approach selected, the choice of screening tool becomes important. Most studies have found that antigenemia assays or PCR assays are comparable for screening patients. The experience at a given center is important in deciding on which of the numerous assays available are best for a given center. Additionally, for how long prophylaxis/pre-emptive therapy should be continued remains controversial. For persons with AIDS, preventive treatment should be continued until the patient is receiving HAART on has a CD4+ lymphocyte count above 100 cells/µL. When to discontinue prevention for transplant recipients is more problematic. Discontinuation of prophylaxis/pre-emptive therapy after 100-120 days has led to late onset CMV disease. In transplant settings the continuation of preventive therapy will be best determined by the clinical status of a given patient and the amount of immunosuppression required. In patients, who remain on high immunosuppression, the risk of CMV remains high and preventive therapy should probably be continued. In contrast, patients following transplantation who are on minimal immunosuppression who are not experiencing GVHD can likely have their CMV preventive treatment discontinued. Monitoring patients for CMV reactivation and increased risk for disease are warranted initially on a monthly basis when preventive treatment is discontinued. CMV血清阳性的晚期AIDS患者（CD4+淋巴细胞小于50个/μL）及血清阳性的器官移植患者（受者或供者CMV血清阳性）是予抢先治疗还是普遍预防治疗目前仍有争议（168）。临床决策时应考虑以下问题：疗效、疗程、费用、后备条件、疾病的相对危险度和治疗的积极程度。在HAART时代，患者经有效抗逆转录病毒治疗后常可避免抢先治疗。若需抢先治疗，则选择何种监测方法至关重要。许多研究表明病毒抗原血症检测或PCR检测是较为可靠的监测方法。临床医师应了解所在临床中心那种检测方法最佳。另外，预防/抢先治疗的疗程仍有争议。在AIDS患者，当HAART治疗后，CD4+淋巴细胞升至100个/μL以上，可停用预防治疗。移植患者何时停止预防/抢先治疗尚缺乏明确观点，在应用100-120天后停止治疗有可能导致后期CMV感染。因此移植患者预防治疗疗程应根据各自的临床情况和免疫缺陷状态来决定。严重免疫缺陷患者CMV感染风险高，应予预防治疗，而那些免疫缺陷较轻微且无GVHD的移植患者，可考虑停用预防治疗，但须每月进行监测，评价免疫状态、明确有无CMV再激活。 The benefit of ganciclovir treatment for infants with congenital CMV remains controversial and awaits well-controlled clinical trials. Despite the lack of such studies, some clinicians are increasingly using prolonged intravenous ganciclovir in infants with symptomatic congenital infection (6 weeks to 6 months). The long-term benefits of such interventions, as well as the possible long-term toxicities, are unknown; thus, such treatment should be considered experimental. Similarly, the use of CMV immunoglobulin to prevent or treat congenital CMV infection is controversial and awaits a controlled clinical trial before such an approach can be recommended. 更昔洛韦治疗婴幼儿先天性CMV感染疗效明确，需随机对照研究进一步评价。尽管缺乏循证医学证据，已经有越来越多的临床医生应用静脉注射更昔洛韦治疗症状性先天性感染的患儿（6周到6个月）。这种经验性治疗的长期获益或药物潜在毒性程度目前仍缺乏相关研究资料。同样，CMV免疫球蛋白预防或治疗先天性感染的疗效不明确，在推荐临床使用之前需对照临床研究进一步评价。
Tables Table 1. Clinical and Laboratory Findings Associated with CMV Polyradiculopathy in Patients with AIDS Table 2. Usual Dosages of Antiviral Drugs for Treatment of CMV Infections in Adults and Children with Normal Renal Function. [Download PDF] Table 3. Ganciclovir Dose Modification in Renal Failure [Download PDF]Table 4. Foscarnet Dose Adjustment in Renal Failure [Download PDF] Table 5. Characteristics of Viral Markers in Predicting CMV Disease in Organ Transplant Recipients [Download PDF]
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