EB病毒感染

译者：孙玲博士

协和医科大学临床医学专业

审阅者：王焕玲教授

北京协和医院感染科

Epstein-Barr virus (EBV; Human herpesvirus-4) is a human gammaherpesvirus that establishes lifelong infection in B lymphocytes with predilection for latent, rather than lytic, infection. EBV replicates during lytic infection by mechanisms common to all herpesviruses, and EBV lytic infection is inhibited by nucleoside analogues such as acyclovir, ganciclovir, and foscarnet. However, diseases induced by EBV are frequently associated with latent infection, and nucleoside analogues active against lytic replication may not be effective clinically. Currently, treatment of EBV-associated diseases is more often directed against virus-induced tumors or disease symptoms and less frequently against viral replication. Pharmacologic intervention in pathways important for latent infection, vaccines and other immunologic therapies to prevent infection or attenuate disease are potential areas for therapeutic development.

EB病毒(人疱疹病毒-4型)是一种能引起B淋巴细胞终生感染的人类γ疱疹病毒, 大多数为潜伏感染，少数为活动性感染(lytic infection，又译作裂解感染)。EB病毒在活动性感染期的复制过程和其它疱疹病毒相同，可以被核苷类似物如阿昔洛韦、更昔洛韦或膦甲酸等抑制，但核苷类似物对最常见的潜伏感染病原体疗效差。目前治疗EB病毒相关疾病以针对病毒诱导的肿瘤和对症治疗为主，其次才为抑制病毒的复制。干预潜伏感染的重要环节的药物、预防感染和控制疾病的疫苗和其它免疫治疗策略等是未来治疗领域研发的重点。

Epstein-Barr virus is a double-stranded DNA virus (reviewed in (69, 70). Human and primate B lymphocytes and to a lesser degree, epithelial cells can be infected in vitro with EBV. After adsorption to the cell surface receptor and virion entry, several Epstein Barr nuclear antigens (EBNAs) and latent membrane proteins are expressed (1). Infected B lymphocytes become immortalized and proliferate indefinitely in culture. The molecular mechanisms by which EBV latent infection gene products immortalize B cell growth are currently being delineated. In general these involve viral proteins usurping normal cell signaling pathways involved in cell growth, such as the Tumor Necrosis Factor Receptor and Notch ligand receptor pathways. Determining how latent EBV genes function to affect cell growth is an active area for investigation and may provide novel opportunities for pharmacologic intervention in EBV latent infection and associated malignancies. In vitro, only a small fraction of infected cells reactivates lytic infection to produce infectious virions. In latently EBV-infected cells, the virus exists as a circular DNA molecule, or episome, in the nucleus, and viral DNA is replicated in unison with cell DNA and cell doubling.

EB病毒是双链DNA病毒(69, 70)，在体外可感染人和灵长类动物的B淋巴细胞和上皮细胞。病毒与细胞表面受体结合、释放病毒颗粒入细胞后, EB核抗原和潜伏膜蛋白在细胞内表达（1）。受染的B细胞则长期存活并在培养中无限复制，EB病毒潜伏感染基因产物引起B细胞无限增殖的分子学机制目前正在研究中，总体上病毒蛋白可能通过侵犯TNF和Notch配体受体等途径干扰细胞生长过程中的正常调节信号通路，导致B淋巴细胞异常增生。潜伏期EB病毒基因对细胞生长的作用机制是研究重点，对于进一步研究阻断潜伏感染和阻断继发肿瘤十分重要。在EB病毒潜伏感染细胞内，病毒以环状DNA分子或游离基因存在于核内，病毒DNA与宿主细胞DNA同時复制、细胞倍增同步。

Infection with EBV is ubiquitous, with 90-95% of all adults displaying serological evidence of past infection (32). In the United States, approximately 50% of children are seropositive by age five, with a second period of seroconversion occurring in early adulthood (64). Infection occurs earlier in developing countries and in certain areas of the United States. Most cases of EBV infection are transmitted by the presence of virus in oropharyngeal secretions of asymptomatic shedders. Blood transfusions and transplantation of solid organs or bone marrow may also be associated with EBV transmission.

EB病毒感染非常普遍，90%-95%成人的血清学检查提示存在既往感染(32)。50%美国儿童5岁时已轉血清学阳性，其余多在成人在其转为抗体阳性(64)；发展中国家及美国某些地区，EB病毒感染发生则更早。多数EB病毒感染通过无症状携带者的口咽分泌物传播，也可通过输血、实体器官及骨髓移植來传播。

Infectious Mononucleosis: Infectious mononucleosis, the syndrome characterized by a classic triad of fever, sore throat and lymphadenopathy (see Clinical Manifestations below) is most commonly caused by primary EBV infection. Infectious mononucleosis is most frequently diagnosed in industrialized countries in young adults. When infection is delayed beyond childhood, the incidence of symptomatic infectious mononucleosis has been estimated to be between 25-75% (59, 77). The higher incidence in this demographic group most likely reflects a later age of primary infection as well as greater access to health care and availability of specific diagnostic tests. Although racial differences in the incidence of infectious mononucleosis have been noted, these are likely to be related to differences in the age at which primary infection occurs (31). Genetic polymorphisms in the interleukin-10 gene have been linked to severe symptomatic EBV infection (30). A recent study also found a significant association of type 1 EBV with infectious mononucleosis, suggesting that viral determinants may also influence the host response that results in symptomatic infection (14). In a large study of students entering college in the United Kingdom, EBV infection was significantly more common among women than men. A history of sexual intercourse was also significantly associated with prior infection as well as with symptomatic infectious mononucleosis (15). EBV is found in the saliva for extended periods after recovery from infection, and has been detected at high titers for median period of 32 weeks after primary infection (5), suggesting that healthy convalescent patients may be a common source of infection among young adults. It has been suggested that larger infectious doses of EBV that may be transmitted in saliva during kissing are responsible for the association of infectious mononucleosis with a history of sexual activity (14).

传染性单核细胞增多症：经典的传染性单核细胞增多症的三大临床表现包括发热、咽痛和淋巴结肿大(见临床表现部分)，在原发EB病毒感染中常见。传染性单核细胞增多症最常见于发达国家的年轻成人。如果原发EB病毒感染延迟到成年后发生，25～75％病人出现传染性单核细胞增多症的临床症状(59, 77)。这种分布区域上的特点一定程度上反映了人群原发感染时年龄、医疗服务的普及和特异性诊断试验的应用。尽管不同种族有发病率不同的报道，但這似乎和发生原发感染时的年龄关系更密切(31) 。有学者认为IL-10基因多态性可能与重症EBV感染相关(30) 。最近一项研究发现1型EB病毒感染与传染性单核细胞增多症有明显的关系，這提示了可能存在着病毒方面的决定因素，可以影响宿主的反应，导致症状性感染(14)。在一项英国大学新生中进行的大规模调查表明，女性的EB病毒感染比男性常见。性生活史也和EB病毒既往感染、传染性单核细胞增多症显著相关。EB病毒可在感染恢复后患者的唾液中存在很长时间，在原发感染后平均32周时唾液中仍能检出高滴度的病毒(5)，提示健康的恢复期患者可能是年轻成人的重要传染源。有研究表明了唾液中大量具有传染性的EB病毒在性生活时可通过接吻传播，导致传染性单核细胞增多症(14)。

Oral Hairy Cell Leukoplakia: Oral hairy leukoplakia is an irregular white oral lesion that is almost exclusively seen in patients with advanced HIV infection or immunosuppression. The major risk factor is low CD4 counts (<200) and the incidence of oral hairy leukoplakia has declined with highly active antiretroviral therapy.

口腔黏膜毛状白斑病：口腔黏膜毛状白斑病表现为口腔不规则白色病损，几乎均出现于晚期HIV感染或免疫抑制的患者，主要危险因素是CD4 T细胞计数低(<200/mm3)，经抗逆转录病毒药物治疗后這毛状白斑发病率可降低。

EBV-Associated-Lymphoproliferative Diseases: EBV-associated lymphoproliferative disease occurs after both solid organ and hematopoietic stem cell transplantation and is most common in the first year post-transplant (23). Post-transplant lymphoproliferative disease (PTLD) occurs in as many as 10% of solid organ transplant recipients and is the leading cause of post-transplant mortality in many settings. The risk is highest with prolonged and intense immunosuppression and in EBV seronegative recipients of organs from EBV-positive donors.. Small bowel, lung, and heart transplant recipients are at highest risk. PTLD after hematopoietic stem cell transplantation occurs almost exclusively in allogeneic transplants. Risk factors include T cell depletion, treatment with anti-thymocyte globulin and HLA-mismatched donor-recipient pairs. Diffuse large B cell lymphoma in AIDS patients is also associated with more prolonged immunosuppression manifested by low CD4 counts. Virtually 100% of primary CNS lymphomas that develop in the setting of HIV infection are EBV-positive versus approximately 75% of peripheral lymphomas.

EB病毒相关的淋巴细胞增生殖疾病：多于实体器官移植或造血干细胞移植后一年内发生(23)。移植后淋巴细胞增生疾病(PTLD)可发生于10%的实体器官移植受者，在移植中心是移植受者死亡的首要原因。在长期大剂量免疫抑制治疗和接受EB病毒血清阳性供者器官的EB病毒血清阴性受者中，风险最高。尤其在小肠、肺和心脏移植的受者危险性最大。造血干细胞移植后PTLD几乎全部发生于异基因移植。其危险因素包括T细胞去除、抗胸腺细胞免疫球蛋白治疗和HLA不匹配。AIDS患者发生弥漫大B细胞淋巴瘤也与以低CD4计数为表现的长期免疫抑制相关。事实上，合并原发中枢神经系统淋巴瘤的HIV感染者100%为EB病毒阳性，而外周淋巴瘤患者中仅75%EB病毒阳性。

X-Linked Lymphoproliferative Disease: X-linked lymphoproliferative syndrome (XLP) is associated with a rare genetic disorder which occurs with a frequency of less than 1 in 1 million. Approximately 50% of cases appear to represent spontaneous mutations without a familial history.

X-连锁淋巴增殖疾病：X-连锁淋巴增殖综合征(XLP)与罕见的基因异常相关，发病率小于百万分之一。在50%的病例中，这种基因异常是由自发突变导致，并非家族遗传。

EBV-Associated Malignancies (Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin’s lymphoma): The endemic form of Burkitt lymphoma originally identified in sub-Saharan Africa is associated with EBV infection in >90% of cases. Sporadic Burkitt lymphoma in the United States is less frequently EBV-associated (<25%) and is relatively rare with an age-adjusted incidence of approximately 0.3 per 100,000 person-years (55). Burkitt’s lymphoma occurs more often in males and in children than in adults.

EB病毒相关恶性肿瘤(Burkitt’s 淋巴瘤,鼻咽癌,霍奇金淋巴瘤)：最初发现于撒哈拉以南的非洲地区的地方性Burkitt’s 淋巴瘤病例中，90%和EB病毒感染有关；美国散发性Burkitt’s 淋巴瘤患者的和EB病毒感染有关的病例不足25%，其年龄校正发病率约0.3/100000人年(55)，相对罕见。Burkitt’s 淋巴瘤在男性和儿童相对高发。

Hodgkin’s lymphoma is a lymphoma of B cell origin that occurs worldwide. Specific subtypes of Hodgkin’s lymphoma, (mixed cellularity and lymphocyte-depleted), are associated with EBV infection. It is now clear that not only is infectious mononucleosis a risk factor (RR=4.0) for the development of Hodgkin’s lymphoma, but that infectious mononucleosis does not increase the risk of EBV-negative Hodgkin’s disease. The median interval to the diagnosis of Hodgkin’s disease after symptomatic infectious mononucleosis was 4.1 years in a large recent study (35).

霍奇金淋巴瘤是B细胞起源淋巴瘤，世界各地均有发病，某些亚型的霍奇金淋巴瘤（混合细胞型及淋巴细胞缺失型）与EB病毒感染相关。目前已明确虽然传染性单核细胞增多症是霍奇金淋巴瘤的危险因素(相对危险度RR=4.0)，但這传染性单核细胞增多症并不增加EB病毒阴性的霍奇金病的风险。近期一项大规模研究表明从症状性传染性单核细胞增多症到诊断霍奇金病的中位时间为4.1年(35)。

Nasopharyngeal carcinoma is rare worldwide, with an incidence of less than one per 100,000, but occurs commonly in localized geographic regions in Southeast Asia and Africa with an incidence as high as 50 per 100,000 in some regions of Southern China (63). In addition to complex genetic susceptibility patterns, epidemiologic evidence implicates dietary factors such as the consumption of salted fish in the etiology of nasopharyngeal carcinoma (40, 90).

在全世界范围内，鼻咽癌是罕见的，其发病率小于十万分之一。但在东南亚和非洲地区其发病率甽较高，而中国南方部分地区发病率可高达十万分之五十(63)。流行病学证据表明除复杂的基因易感型外，鼻咽癌发病可能还与饮食因素如喜食咸鱼等相关(40, 90)。

Chronic Active EBV Infection: EBV infection rarely causes an aggressive syndrome with persistent lytic replication and widespread organ involvement. This rare manifestation most likely represents an inability of the host to adequately contain the primary infection and may reflect underlying specific immune deficits. Chronic Fatigue Syndrome: EBV has also been implicated as a cause of the much more common chronic fatigue syndrome. However, seroepidemiologic studies have argued against a pathogenic role for EBV in chronic fatigue syndrome (36, 37).

慢性活动性EB病毒感染:： EB病毒感染引起持续的病毒复制后产生溶细胞反应，使得多脏器受累的情况非常罕见，其出现常提示宿主无法控制原发感染，有特殊的免疫功能缺陷存在的可能。慢性疲劳综合征：虽然EB病毒感染被认为是慢性疲劳综合征的一个常见病因，但血清流行病学研究结果并不支持这种观点(36, 37)。

Epstein-Barr virus is associated with a variety of clinical disorders arising from different pathogenic mechanisms (reviewed in (69). Infection during childhood is often asymptomatic or associated with nonspecific symptoms.

EB病毒通过不同的发病机制可引起多种临床疾病(69)。儿童时期的感染通常无症状或没仅有非特异的临床表现。

Infectious Mononucleosis: Infection during adolescence or adulthood more commonly results in the syndrome of acute infectious mononucleosis, characterized by a vigorous humoral and cellular immune response to rapidly proliferating EBV-infected B cells. Epidemiologic evidence suggests that the incubation period of infectious mononucleosis is greater than 4 weeks. The most common symptoms are sore throat, fever and lymphadenopathy. The exudative pharyngitis is often severe and associated tonsillar swelling can cause difficulty swallowing. Fever is almost universal, and lymphadenopathy is present in approximately 90% of patients at some point during the course of the illness. Headache, anorexia, malaise and fatigue are common. Less common symptoms present in less than 25% of cases include parotitis, conjunctivitis and myalgias. Lymphadenopathy is most commonly cervical but can also be generalized. The enlarged nodes are mobile and only mildly tender. A rash that is usually non-pruritic is seen in less than 10% of patients. Administration of ampicillin during the course of illness leads to a typical pruritic, maculopapular eruption that can be diffuse. Splenic enlargement is common and has been reported to be detectable by physical examination in 15-50% of patients in various studies. However, based on ultrasound examination, splenic enlargement is probably universal. Hepatic enlargement is less common and less prominent. Palatal enanthems and jaundice occur in less than 10-15% of patients. Asymptomatic elevations in transaminases occur in the majority of patients. Many aspects of this clinical syndrome, e.g. fever, lymphadenopathy, splenomegaly, atypical lymphocytosis, are due to the vigorous NK and T cell proliferation and cytokine response of the immune system rather than direct viral infection, replication, and cytolysis.

传染性单核细胞增多症：青春期或成人感染EB病毒常可出现急性传染性单核细胞增多症表现，以EB病毒感染B细胞产生强烈的体液和细胞免疫反应为特征。流行病学证据提示传染性单核细胞增多症潜伏期大于4周，常见症状为咽痛、发热和淋巴结肿大。渗出性咽炎常较严重，扁桃体肿大可有吞咽困难。发热最常见；约90%的患者出现淋巴结肿大，淋巴结肿大多累及颈部淋巴结，也可累及全身，可活动、轻度压痛。此外头痛、食欲不振和乏力等也较常见；25%的患者出现腮腺炎，结膜炎或肌痛不常见；出现皮疹的患者不足10%，多不痒，若病程中曾服用阿莫西林可出现弥漫的典型斑丘疹，伴瘙痒；15-50%的患者体格检查可见脾大，若行超声检查可发现感染者脾脏增大普遍存在；肝大是較少见也較不严重的，小于10-15%的患者可出现黄疸或上鄂黏膜疹，多数患者可有无症状的转氨酶升高。大多临床表现如发热、淋巴结肿大、脾大及异型淋巴细胞增多由NK细胞和T细胞增生、免疫系统细胞因子应答造成，并非直接由病毒感染、复制和溶细胞作用引起。

The syndrome of mononucleosis with atypical lymphocytosis can also be seen during primary infection with several other viruses including human cytomegalovirus, HIV, and human herpesvirus 6 (HHV-6), with CMV being the most common. Toxoplasmosis is another less common cause of a mononucleosis-like syndrome with lymphadenopathy.

伴有异型淋巴细胞增多的单核细胞增多征还可见于其它多种病毒感染，如人巨细胞病毒(CMV)、HIV、人疱疹病毒-6感染，其中CMV感染最常见。弓形虫感染也可引起淋巴结肿大等单核细胞增多症样的表现，但较少见。

Occasional serious and life-threatening complications of EBV infection occur and include autoimmune hemolytic anemia, erythrophagocytic syndrome, thrombocytopenia, splenic rupture and neurologic syndromes (81). The latter, although rare, include encephalitis and Guillain Barre syndrome.

EBV感染偶尔会引起致命的并发症，如自身免疫性溶血、噬血细胞综合征、血小板减少症、脾破裂及神经系统综合征(包括脑炎和格林巴利综合征) (81)等。

Oral Hairy Leukoplakia: Oral hairy leukoplakia is a benign white lesion most commonly seen on the lateral surface of the tongue. Oral hairy leukoplakia is almost exclusively seen in patients with HIV infection and occasionally in patients with other types of chronic immunosuppression. The lesions are not friable and the main differential diagnosis is oral candidiasis. The diagnosis is usually made clinically based on the appearance of the lesion. Biopsies are positive for EBV genomes by in situ hybridization and immunofluorescent staining.

口腔黏膜毛状白斑病：口腔黏膜毛状白斑病是多发生于舌两侧的白色良性病变，不易被擦拭去除，這几乎均发生于HIV感染或免疫抑制患者。口腔黏膜毛状白斑病主要应和口腔念珠菌感染鉴别。诊断主要根据病变的外观。若行病变活检则可经过原位杂交或免疫荧光染色的方法测到EB病毒的基因组。

EBV-Induced Lymphoproliferation: The clinical presentation of PTLD is highly variable (For review see (23). Most cases occur within the first year although cases have been reported nine years after transplantation. Symptoms are similar to those of primary EBV infection and include fever, malaise, and lymphadenopathy. The disease can progress rapidly, underscoring the need for a high index of clinical suspicion in high-risk patients. The lymphoproliferations can range from a polyclonal lymphoproliferation to frank lymphoma. Lymphoma developing in the setting of PTLD is usually of diffuse large-cell type.

EB病毒诱导的淋巴细胞增殖疾病：移植后淋巴细胞增殖疾病(PTLD)临床表现多样(综述参考文献23)，虽有移植后第9年发生PTLD的报道，但PTLD多发生于移植后1年内。症状与原发EB病毒感染相似，如发热、全身不适和淋巴结肿大等，进展可以很迅速，這在高危人群中应予高度的臨床重视。PTLD可为多克隆淋巴增生到淋巴瘤，其中淋巴瘤多为弥漫大细胞型。

Chronic Active EBV Infection: Rare patients have an unusual clinical course following infectious mononucleosis and develop a chronic active infection characterized by ongoing lytic EBV replication and multiple organ system disease, such as pneumonitis, hepatitis, pancytopenia and iritis (78). These patients typically have extremely high antibody responses to EBV early antigens, lack antibodies to EBNA-1, and exhibit severe disease with end organ involvement or evidence of increased viral load in affected tissues (50, 78, 83).

慢性活动性EB病毒感染：极少数患者在传染性单核细胞增多症后发展为慢性活动性感染，表现为持续的EB病毒复制、溶细胞反应和多器官受累，如肺炎、肝炎、全血细胞减少及结膜炎等(78)。这些患者通常有很高的EB病毒早期抗原(EA)抗体滴度並缺乏EB病毒核抗原-1(EBNA-1)抗体，可表现为器官严重受累，或受累组织中病毒载量升高(50, 78, 83)。

X-Linked Lymphoproliferative Disease: Individuals with a rare, inherited X-linked immunodeficiency known as X-linked lymphoproliferative syndrome or Duncan’s syndrome, are at risk for overwhelming lethal primary infection with Epstein-Barr virus (6, 66). The clinical presentation is that of a fulminant infectious mononucleosis syndrome with typical and severe symptoms of infectious mononucleosis. In addition, patients often develop a severe hepatitis usually culminating in fatal hepatic failure. Patients may also develop erythrophagocytic syndrome. Survivors are at risk for the subsequent development of lymphoma and dysgammaglobulinemia. The genetic defect in these patients has been mapped to a small cytoplasmic protein SAP, implicated in regulation of T and NK cell signaling (9). Genetic defects in the SAP gene lead to a defect in the development of NKT cells in both mice and humans, suggesting a mechanism for the development of deficient antiviral responses (8, 58).

X-连锁淋巴增殖疾病：是一种罕见的X-连锁遗传免疫缺陷，又称X-连锁淋巴增生综合征或Duncan’s 综合征，此病患者一旦感染EB病毒可危及生命(6, 66)。表现为严重而典型的爆发性传染性单核细胞增多征，此外还可有重症肝炎导致肝衰、噬血细胞综合征等，存活者有发生淋巴瘤和异常球蛋白血症风险。此病的缺陷基因定位在胞浆蛋白SAP，可导致T细胞和NK细胞的信号通路的调节异常(9)。SAP基因缺陷可导致人和鼠的NKT细胞发育缺陷，从而导致抗病毒反应缺陷(8, 58).

EBV Associated Malignancies (Burkitt’s lymphoma, Nasopharyngeal carcinoma, Hodgkin’s lymphoma): Burkitt’s lymphoma usually presents with lymphadenopathy or an abdominal mass and is much more common in children than in adults . Burkitt lymphoma is an extremely rapidly-growing tumor and disseminated disease involving bone marrow and CNS is common. It should be emphasized that rapid diagnosis and treatment of Burkitt lymphoma is extremely important as the response and cure rate is greater than 70% with appropriate initial therapy whereas salvage therapy is markedly less successful.

EB病毒相关恶性肿瘤(Burkitt’s 淋巴瘤,鼻咽癌,霍奇金淋巴瘤)：Burkitt’s 淋巴瘤通常表现为淋巴结肿大或腹部肿物，儿童较成人常见。Burkitt’s 淋巴瘤生长迅速，常广泛侵犯骨髓或中枢神经系统。早期予以适当治疗，治愈率大于70%，挽救治疗效果差，故早期诊治非常重要。

Hodgkin’s lymphoma usually presents as lymphadenopathy. Mediastinal adenopathy occurs in over 50% of patients and B symptoms such as fever and weight loss are common. Hodgkin’s lymphoma has also been associated with a large variety of unusual paraneoplastic manifestations including skin or CNS abnormalities, nephrotic syndrome, hemolytic anemia and thrombocytopenia. Hodgkin’s lymphoma has a very high cure rate and relapses have been successfully treated with intensive chemotherapy and stem cell transplantation.

霍奇金淋巴瘤通常表现为淋巴结肿大，50%的患者出现纵隔淋巴结肿大；发热及体重下降也较常见。霍奇金淋巴瘤还可合并多种少见的副肿瘤综合征表现，如皮肤受累、中枢神经系统异常、肾病综合征、溶血性贫血或血小板减少等。霍奇金淋巴瘤治愈率很高，复发者对强化治疗和干细胞移植反应也很好。

Nasopharyngeal carcinoma of the undifferentiated type is essentially 100% EBV-associated. As mentioned earlier, this type of nasopharyngeal carcinoma is common in Southeast Asia and is also found in Northern African and Inuit populations but is rare in other geographic areas. Diagnosis is often delayed and patients may present with metastatic head and neck masses. Serological screening or high-risk populations for IgA antibodies against VCA and early antigen allows identification of early cases for close monitoring. Definitive diagnosis requires endoscopic biopsy and demonstration of EBV antigen or Epstein-Barr virus-encoded RNA (EBER) expression in malignant tissue. Endoscopic brushing with measurement of EBV DNA load and specific EBV mRNAs expressed in tumors may allow less invasive diagnostic testing and follow-up (80).

未分化型鼻咽癌均与EB病毒感染相关。如前所述，此型鼻咽癌在东南亚地区多发，在北非和因纽特人群也可出现，但在世界其他地区罕见。往往在出现头部转移灶或颈部肿物后才被诊断。血清学筛查EB病毒衣壳抗原(VCA)和早期抗原(EA)IgA抗体可帮助病例早期筛查核观察。确诊依据内镜活检组织病理，证实肿瘤组织中有EB病毒抗原或EB病毒编码的RNA(EBER)。内镜下毛刷取得肿瘤组织，并进行EB病毒DNA定量和EB病毒特异mRNAs表达的检测不仅可避免更大的有创检查，还可用于随访(80)。

Laboratory confirmation of EBV infection is primarily achieved by serological testing. Heterophile antibodies directed against sheep erythrocyte agglutinins are positive in about 90% during the primary infection. Commercially available Monospot testing for heterophile antibodies is less sensitive in children, and sequential Monospot testing or determination of EBV-specific antibodies is indicated when the clinical findings are suggestive of EBV infection but the initial Monospot is negative.

实验室确诊EB病毒感染主要根据血清学检查。抗羊红细胞凝集素嗜异性抗体在90%的原发EB病毒感染中阳性；商业的嗜异凝集试验在儿童中灵敏性较差，对于临床怀疑EB病毒感染但最初嗜异凝集试验阴性的患者，应连续行嗜异凝集试验或行EB病毒特异性抗体检查。

In the clinical setting in which the young adult patient has typical infectious mononucleosis, a Monospot will confirm the diagnosis in more than 90% of cases. Unless the history suggests the possibility of other infections such as HIV, a battery of viral serologies is not routinely necessary. If the presentation is atypical but suggestive of infectious mononucleosis, and the Monospot is negative, EBV serology can confirm the diagnosis or indicate whether testing for other pathogens such as CMV, toxoplasmosis may be appropriate, based on the clinical presentation and history.

临床上出现典型传染性单核细胞增多症的年轻成人中，90%以上可出现嗜异凝集试验阳性，帮助诊断。除非病史提示患者可能存在其他感染如HIV感染，一系列病毒的血清学检测不做为常规检查，若临床怀疑传染性单核细胞增多症，但症状不典型，嗜异凝集试验检测阴性， EB病毒血清学检查可帮助诊断，结合病史和临床表现必要时筛查其他病原体如CMV、弓形虫等。

The presence of IgM antibodies to viral capsid antigen (VCA) is the most sensitive and specific indicator of acute infection (Table 1). These are usually detectable at the initial presentation, along with IgG VCA Abs. IgM VCA antibodies, however, decline and are absent by 4-8 weeks, whereas IgG VCA Abs persist for life (18, 37). Therefore, IgG VCA antibodies are not usually useful in diagnosing infectious mononucleosis since virtually all patients are IgG positive by the time they seek medical attention. Antibodies to EBNAs do not develop until approximately 4 weeks after onset of symptoms, and persist for life (33). Seroconversion to anti-EBNA positivity is therefore indicative of recent EBV infection. Although antibodies to EBV early antigens are often elevated during acute infection, they may persist for variable periods and are occasionally detectable in healthy convalescent patients many years after infection, and are therefore of limited utility in diagnosing acute infection (37).

病毒衣壳抗原(VCA)IgM抗体的出现是急性感染最灵敏和特异的指标(表1)，在出现症状早期，血中可检出VCA的IgM和IgG抗体，，但IgM在感染4-8周后即转为阴性，而IgG则可终生保持阳性(18, 37)，因此几乎所有就诊的病人IgG抗体均阳性，不能据此诊断传染性单核细胞增多症。抗EB核抗原（EBNA）抗体多于症状出现约4周后出现，可终生阳性(33)，故抗EB核抗原抗体血清学转换提示近期EB病毒感染。在感染急性期，虽然EB病毒早期抗原(EA)抗体滴度常增高，但持续时间不定，偶尔在恢复期的健康人中也可检测阳性，因而对于急性感染诊断的意义有限(37)。

At the time of presentation, VCA IgM antibodies are positive, and VCA IgG and early antigens are also usually positive. As convalescence proceeds, EBNA antibodies become detectable and VCA IgM disappears. EBNA and VCA IgG antibodies remain detectable for life and early antigen antibodies are also usually detectable though at low titers.

在出现临床症状时，VCA IgM抗体阳性，VCA IgG抗体和早期抗原通常也阳性。随着病程进入恢复期，EBNA抗体转为阳性而VCA IgM抗体消失。EBNA和VCA IgG抗体终生保持阳性，EA抗体也常终生保持低滴度阳性。

Post Transplant Lymphoproliferative Disease (PTLD): Quantifying peripheral blood EBV DNA load by polymerase chain reaction is used to identify immunosuppressed patients with or at high risk for developing EBV-associated B cell lymphomas. Although an elevated blood EBV DNA load is clearly associated with the development of PTLD, the predictive value of such a finding is not uniformly high, since only approximately 50% of hematopoietic stem cell transplantation patients with an elevated EBV DNA develop PTLD. An increasing EBV DNA load may be predictive of the development of PTLD, underscoring the need for serial monitoring in high-risk patients.

移植后淋巴细胞增殖性疾病(PTLD)：对于免疫抑制的病人，利用PCR方法进行外周血EB病毒DNA的定量检测可用于发现其EB病毒相关B细胞淋巴瘤或评价其风险。虽然外周血EB病毒DNA定量升高和PTLD明确相关，但在造血干细胞移植患者中，仅50%EB病毒DNA定量升高的病人出现PTLD，因此其阳性预测值并不总是很高。如果EB病毒DNA定量持续增高，可预示出现PTLD的可能加大，用于高危人群监测。

After resolution of primary infection, EBV persists for life as a latent infection in B cells and as a lytic infection in the oropharynx. Persistent EBV infection is controlled by a virus-specific immune response and is asymptomatic in most humans. However, immunosuppression associated with HIV infection, transplantation, or congenital immunodeficiencies can result in uncontrolled oligoclonal or monoclonal B cell proliferation of latently infected cells. Uncontrolled lytic infection in the oropharynx is manifested as oral hairy leukoplakia in immunosuppressed hosts (24). Persistent, latent EBV infection is also associated with development of Burkitt’s lymphoma, nasopharyngeal carcinoma, certain types of Hodgkin’s lymphoma, gastric adenocarcinoma, and leiomyosarcomas in immunosuppressed hosts (38). Infection of NK cells by EBV has recently been associated with hypersensitivity to mosquito bites and the development of NK cell leukemia (41).

原发感染恢复后，EB病毒可在B细胞内以潜伏感染形式终生存在，或在口咽部引起活动性产病毒性感染。由于病毒特异性免疫反应的控制，多数患者的持续EB病毒感染并不出现临床症状。但在因HIV感染、移植或先天免疫缺陷等原因导致的免疫功能抑制人群中，EB病毒感染可引起潜伏感染B细胞寡克隆或单克隆的无限制性增生。在免疫抑制者中，口咽部无限制的EB病毒的活动性产病毒性感染表现为口腔黏膜毛状白斑病(24)；持续潜伏感染则可引发Burkitt’s淋巴瘤、鼻咽癌、某些类型的霍奇金淋巴瘤、胃腺癌和平滑肌肉瘤(38)。近来发现EB病毒感染NK细胞和蚊子叮咬后出现的超敏反应及NK细胞白血病相关(41)。

Patients who experience infectious mononucleosis as a consequence of primary infection may have a long-lasting and possibly permanent down-regulation of the IL-15 receptor IL15Rα on T and NK cells (75). Since IL-15 is involved in the generation and maintenance of memory CD8+ T cell populations, it is possible that symptomatic EBV infection may have long-term effects on immunologic function.

原发EB病毒感染后出现传染性单核细胞增多症的患者可有长期甚至永久的T细胞和NK细胞IL-15受体 IL15Rα 的下调(75)。由于IL-15参与记忆CD8+ T细胞群的传代和维持，所有症状性EB病毒感染可能会对免疫功能产生长期影响。

The pathogenesis of EBV-associated disease is closely correlated with the proliferative stimulus of EBV on the infected cell and the immune status of the host. Thus, EBV causes lymphoproliferative lesions that range from Burkitt’s lymphoma to Hodgkin’s lymphoma or transplant-associated lymphomas. Infection of nasopharyngeal epithelium can lead to nasopharyngeal carcinoma or to hairy leukoplakia in the immunosuppressed host. The pattern of EBV latent infection gene expression in each of these diseases is distinct (1). Many of the proteins expressed by EBV have been identified as having either growth-promoting, anti-apoptotic or immune evasion function. Vaccination, immunomodulation, or pharmacologic intervention of important cell-signaling pathways usurped by viral gene products might provide more effective therapeutic strategies against EBV-associated malignancies than traditional anti-viral drugs designed to block viral replication.

EB病毒相关疾病的发病机制与EB病毒对感染细胞引起的增殖刺激反应的大小和宿主的免疫状态紧密相关。EB病毒可诱发产生严重的淋巴细胞增殖病变，如Burkitt’s淋巴瘤、霍奇金淋巴瘤或移植相关淋巴瘤。免疫抑制宿主鼻咽部上皮细胞EB病毒感染可导致鼻咽癌或黏膜毛状白斑病。不同疾病中潜伏感染的EB病毒基因表达不同(1)，多种EB病毒表达的蛋白已被证实具有促进生长、抗凋亡或免疫逃逸等的功能。在EB病毒相关恶性肿瘤的治疗方面，疫苗、免疫调节或药物如能纠正被病毒基因产物所改变的细胞信号传导异常，则可能显著提高疗效，因为传统抗病毒药物只能阻止病毒复制，对于EB病毒相关肿瘤的临床疗效十分有限。

Review Article: Macsween KF, Crawford DH. Epstein-Barr virus-recent advances. Lancet Infect Dis. 2003 Mar;3:131-40.

Review Article: Funk GA, et al. Viral dynamics in transplant patients: implications for disease. Lancet Infect Dis 2007;7:460-472.

SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo

Because EBV infection typically results in latent infection, rather than a lytic infection associated with plaque formation, EBV sensitivity to conventional antiviral drugs cannot be assayed by conventional plaque reduction assays. Instead, latently infected cell lines are used in which cells can be induced for lytic viral replication in the presence or absence of potential antiviral agents. Antiviral activity is measured by quantifying viral DNA and is expressed as the concentration of drug required to inhibit 50% of viral DNA replication induced by lytic infection (IC50). Using these types of assays, acyclovir has an IC50 of 0.3 uM for EBV, and ganciclovir has an IC50 of 0.05 uM for EBV (11, 42, 47). It was originally hypothesized that acyclovir was effective against EBV in the absence of an EBV-specified thymidine kinase (61), but EBV does encode a thymidine kinase (BXLF1) that was belatedly discovered due to the difficulties of inducing EBV lytic replication in vitro (48). The EBV thymidine kinase shares approximately 50% amino acid similarity with the HSV thymidine kinase and can utilize acyclovir and ganciclovir as substrates. Similarly, the EBV DNA polymerase shares approximately 70% amino acid similarity with the HSV DNA polymerase reflecting the common heritage of lytic replication mechanisms. The conserved mechanisms of lytic replication among herpesviruses suggests that other antiviral drugs developed against herpes simplex or cytomegalovirus replication may have activity against EBV lytic infection.

由于EB病毒原发感染后多转为潜伏感染；引起溶细胞作用、导致细胞死亡則是少见的，所以EB病毒对传统抗病毒药物的敏感性不能利用细胞死亡的减少这种常规检测方法进行评价，而是比较抗病毒药物存在与否时，潜伏感染细胞株可诱导出现溶细胞性病毒复制的变化进行评估。抗病毒活性用IC50表示，是指能够使病毒产生溶细胞性复制减少50%时的血药浓度。此方法检测的阿昔洛韦抗EB病毒IC50值为0.3 uM，更昔洛韦为0.05 uM(11, 42, 47)。最初曾认为阿昔洛韦在无EB病毒特异性胸苷激酶时仍有抗EB病毒作用(61)，但后来研究发现EB病毒仍可编码胸苷激酶(BXLF1) (48)，先前未被发现主要是由于EB病毒体外诱导溶细胞性复制是非常困难的。约50%EB病毒胸苷激酶的氨基酸序列与单纯疱疹病毒（HSV）相同，均可利用阿昔洛韦或更昔洛韦作为底物。同样，约70%EB病毒DNA聚合酶氨基酸序列和HSV相同。反映两种病毒存在相同遗传基础，决定其产生溶细胞性复制的机制。这种决定产生溶细胞性复制的遗传基础提示其它具有抗HSV或CMV复制的药物也可能同样具有抑制EB病毒产生活动性产病毒性感染的作用。

Despite the effectiveness of acyclovir against EBV lytic replication, acyclovir has no inhibitory activity on replication of the episomal EBV genomes present in latent infection. Thus, acyclovir will inhibit production of linear genomes in the minority of cells entering lytic infection in an EBV-infected B cell line, but episomal DNA is replicated by cell DNA polymerases and is unaffected by acyclovir in the majority of EBV-infected B cells that are latently infected. Once acyclovir is removed, lytic replication can resume from the latent EBV genomes (10, 61). Thus, immortal B cell growth induced by latent EBV infection is unaffected by acyclovir treatment in vitro, and these in vitro studies are consistent with the clinical experience that nucleoside analogues have little effect on EBV-induced malignancies associated with latent EBV infection.

尽管阿昔洛韦能有效抑制EB病毒溶细胞性复制，但对于潜伏感染细胞中EB病毒游离基因组的复制无抑制作用。因此阿昔洛韦只可抑制小部分进入活动期的EB病毒，对于大多数处于潜伏感染期的B细胞中的病毒DNA复制无抑制作用。一旦停药，潜伏的EB病毒基因组可转而进入活动复制阶段、溶解细胞(10, 61)。体外研究发现由EB病毒潜伏感染诱导的B细胞的持续生长不受阿昔洛韦影响，这个结果和临床核苷类似物治疗EB病毒潜伏感染相关的恶性疾病无效是一致的。

The issue of whether nucleoside analogues might be effective during primary gammaherpesvirus infection, where viral replication is more likely to play an important pathogenic role, has been extensively studied in infectious mononucleosis. In 6 different studies involving a total of approximately 320 patients, oral or intravenous acyclovir therapy consistently reduced or eliminated lytic EBV infection during therapy as detected by virus shedding in oropharyngeal secretions but had no effect on clinical outcome, duration of symptoms, or establishment of persistent infection in the oropharynx or peripheral blood B lymphocytes (2, 3, 62, 86, 87, 89). Thus, acyclovir can effectively inhibit lytic EBV replication in vivo, but acyclovir treatment initiated after the onset of symptoms has no clinical benefit in infectious mononucleosis most likely because latent infection has already been established and the vigorous host immune response to virus infection responsible for the majority of symptoms has been triggered.

由于在原发γ疱疹病毒感染中，病毒复制是重要的致病因素，核苷类似物对于原发感染是否有效的很多研究来源于对传染性单核细胞增多症的治疗经验。在6项总共包括了320名病人的不同研究中，通过检测口咽分泌物中病毒的水平发现口服或静脉阿昔洛韦治疗可降低或者消灭EB病毒活动性产病毒性感染；但并不能改善临床转归、缩短症状持续的时间或减少口咽及外周血B淋巴细胞内持续感染的形成(2, 3, 62, 86, 87, 89)。因为大部分传染性单核细胞增多症的症状是由病毒感染后触发的宿主免疫反应所引起，这时潜伏感染已经形成，所以在出现临床症状后给予阿昔洛韦治疗只能抑制EB病毒体内溶细胞性复制，无法改善临床症状。

In rare, complicated cases of primary EBV infection and infectious mononucleosis where the patient is immunosuppressed or severely ill, acyclovir or ganciclovir treatment may be rational given the safety profile of these drugs, its ability to inhibit EBV replication in vitro and in vivo, and anecdotal reports of clinical response in unusual cases where excessive EBV replication may have been pathogenic (16, 39, 60, 78).

少见情况下，如免疫抑制或病重者出现的原发EB病毒感染或传染性单核细胞增多症，病情复杂，有报道认为这种情况下EB病毒的过份复制可能成为致病因素(16, 39, 60, 78)，可以选择给予阿昔洛韦或更昔洛韦治疗，原因是这些药物安全性好，体内、体外均证实有抑制EB病毒复制作用。

Oral hairy leukoplakia is an unusual lesion of the tongue found in HIV-infected patients. Vigorous EBV lytic replication is present in the excessively proliferating epithelium. This is the only instance where disease appears to be a direct consequence of lytic EBV replication, and oral acyclovir therapy (3.2 gm/day) can temporarily reverse the lesions (68). However, recurrence could be due to reactivation of persistent infection or reinfection lytic EBV replication and oral hairy leukoplakia frequently recur upon withdrawal of therapy.

口腔粘膜毛状白斑一种出现予HIV感染者舌部的特殊病变，在过度增殖的上皮细胞内EB病毒存在活跃的溶细胞性复制。口腔粘膜毛状白斑是唯一由EB病毒溶细胞复制直接引起的病变，口服阿昔洛韦(3.2 g/天)可暂时控制病灶(68)。但因潜伏感染活动而再次出现EB病毒溶细胞性复制，停药物后口腔粘膜毛状白斑常常复发。

EBV-infected monoclonal or polyclonal B cell proliferations can arise during immunosuppression associated with congenital immunodeficiencies, transplantation, or HIV infection. Since latent EBV infection is responsible for driving uncontrolled B cell growth, nucleoside analogues generally are not effective against such lymphoproliferative disease. While there are case reports that early, polyclonal EBV-induced B cell proliferations may respond to nucleoside analogues (27, 29) more aggressive or monoclonal EBV-induced B cell lymphoproliferations are generally not responsive to acyclovir (28, 29, 82). Some have suggested that a more active nucleoside analogue such as ganciclovir might be more effective against EBV-induced B cell lymphoproliferations. However, there is limited evidence to support this hypothesis, and it is counter-intuitive to the underlying pathogenesis of latent EBV infection. Phase II/III clinical trials are underway to assess the feasibility of chemically inducing lytic gene expression in the proliferating EBV-infected cells in lymphoproliferative disease and killing the induced cells with ganciclovir. Specifically, EBV thymidine kinase expression may be induced in EBV-infected cells by treatment with arginine butyrate, rendering the cells susceptible to killing by ganciclovir (19). There are no currently available antiviral agents that have been clinically demonstrated to be effective against latent EBV infection.

在患有先天性免疫缺陷、移植或HIV感染等免疫抑制病人中，EB病毒感染的B细胞可发生单克隆或多克隆增殖。由于潜伏感染导致了B细胞的无限制生长，故核苷类似物对于治疗EB病毒相关的淋巴细胞增殖性疾病无效。曾有病例报道核苷类似物可治疗EB病毒诱导的早期的、多克隆B细胞增殖(27, 29)，但阿昔洛韦治疗更具侵袭性的、单克隆EB病毒诱导的B细胞增殖无效(28, 29, 82)。也有学者建议使用作用更强的核苷类似物，如更昔洛韦，认为可能对于抑制EB病毒诱导的淋巴细胞增殖有效，但支持这种建议的证据非常有限，且与目前认为的发病机制不符。在目前临床正在进行的有关更昔洛韦疗效的II/III期临床实验中，淋巴增殖性疾病的正在增殖的EB病毒感染细胞先被利用化学方法进行诱导，促使其表达产生溶细胞性复制的基因后，再研究更昔洛韦杀伤这些被诱导的细胞的作用，从而评定其用于治疗EB病毒引起的淋巴细胞增殖性疾病的可行性。特别是，经精氨酸丁酸盐处理后的EB病毒感染细胞可以表达EB病毒胸苷激酶，使得这些细胞变得对更昔洛韦敏感而被杀灭(19)。目前为止，临床上尚无有效治疗EB病毒潜伏感染的药物。

Both clinical responses and failures with acyclovir or corticosteroids have been noted in anecdotal reports of these rare patients with chronic active EBV infection (78, 84). A placebo controlled study with acyclovir has shown no efficacy for patients with chronic fatigue syndrome (85).

慢性活动性EB病毒感染病例罕见，相关报道中关于阿昔洛韦或糖皮质激素的疗效结论缺乏一致性(78, 84)。一项安慰剂对照研究发现阿昔洛韦治疗慢性疲劳综合征无效(85)。

EBV-Associated Malignancies (Burkitt’s Lymphoma, Nasopharyngeal Carcinoma, Hodgkin’s lymphoma)

EB病毒相关恶性肿瘤(Burkitt’s 淋巴瘤,鼻咽癌,霍奇金淋巴瘤)

There is no effective antiviral therapy for the Burkitt’s lymphomas, nasopharyngeal carcinoma, and Hodgkin’s lymphoma associated with EBV infection, and treatment is usually based upon cancer chemotherapy. Adoptive transfer of EBV-specific cytotoxic T lymphocytes may also be useful for treating these types of EBV-associated malignancies (73). Boosting of the immune response to EBV latent antigens by expressing these genes in dendritic cells may offer promise for treatment of relapsed Hodgkin’s lymphoma (21). Novel pharmacologic approaches against latent EBV infection may be another approach for treating these diseases. Antisense oligonucleotides may be used to disrupt specific essential latent gene functions, such as EBNA-1 binding and maintenance of the latent EBV episome (43). Delineation of the cell signaling pathways used by EBV latent genes, such as the Tumor Necrosis Factor Receptor pathway by LMP1 (56), may provide unique opportunities to block virus induced cell proliferation or to induce apoptosis of virus infected cells.

治疗EB病毒相关的Burkitt’s 淋巴瘤、鼻咽癌、霍奇金淋巴瘤主要依靠肿瘤化疗，抗病毒治疗无效。输入EB病毒特异性细胞毒性T细胞的可能对于治疗这些EB病毒相关恶性肿瘤有效(73)；通过树突状细胞表达EB病毒潜伏感染抗原而刺激机体对病毒潜伏感染抗原的免疫反应，可能将来成为治疗霍奇金淋巴瘤复发的有效方法(21)；针对EB病毒潜伏感染的新药可能为这些疾病提供另一种选择；反义寡核苷酸可用于干扰潜伏感染基因特异的所必需的功能，如EB核抗原-1的结合和这些潜伏EB病毒基因的保持(43)；阻断EB病毒潜伏基因所需的细胞信号通路，如潜伏膜蛋白1(Latent Membrane Protein, LMP1)阻断肿瘤坏死因子受体通路(56)，可成为阻碍病毒诱导细胞增殖或诱导细胞凋亡的独特方法。

Treatment of EBV-associated diseases is closely linked to the underlying pathogenesis of the disease.

Supportive treatment is generally indicated since more than 95% of infectious mononucleosis cases resolve uneventfully without specific therapy. Acetaminophen can be used to reduce fever. Use of concomitant antibiotics for possible bacterial pharyngitis should be judicious and supported by positive culture results due to the high incidence of allergic reactions to antibiotics such as ampicillin during acute infectious mononucleosis.

支持治疗：95%的传染性单核细胞增多症不经特殊治疗自行缓解，不出现并发症，故常给予支持治疗。可用乙酰氨基酚退热。对于可能合并细菌性咽炎的病例应慎重加用抗生素，因为急性传染性单核细胞增多症病人容易发生抗生素过敏反应，如阿莫西林，在细菌培养有阳性结果时则支持临床加用抗生素。

The use of corticosteroids for uncomplicated infectious mononucleosis is still controversial. Corticosteroids have been shown to reduce fever and shorten the duration of constitutional symptoms (7, 12, 45, 65, 79). However, adverse drug complications can arise from even short courses of corticosteroid use (12, 88), and corticosteroid use is probably best avoided for routine infectious mononucleosis, a self-limited disease. Corticosteroid use is generally reserved for infectious mononucleosis cases complicated by potential airway obstruction from enlarged tonsils, severe thrombocytopenia, or severe hemolytic anemia (13, 65, 81). These complications result from the excessive immune response to virus infection rather than uncontrolled viral infection, and a short course of corticosteroids at 1 mg/kg/day of prednisone with tapering over 1-2 weeks can be effective for treating the excessive tonsillar proliferation or autoimmune symptoms. Corticosteroids might also be used for other autoimmune complications rarely associated with infectious mononucleosis such as CNS involvement, myocarditis or pericarditis (49). Unless contraindicated, it is our general practice to administer acyclovir concurrently with corticosteroids.

糖皮质激素在治疗无并发症的传染性单核细胞增多症上尚存争议。糖皮质激素可退热、缩短全身症状的病程(7, 12, 45, 65, 79)，但即使短期应用也可出现药物副作用(12, 88)，由于传染性单核细胞增多症通常为自限性，普通病例最好避免使用糖皮质激素。糖皮质激素应用指征仅限于出现并发症的病例，如严重肿大扁桃体有可能导致气道梗阻、严重血小板减少或严重溶血性贫血(13, 65, 81)。这些并发症的发生是由病毒感染诱发的过度全身免疫反应导致，并非不能控制的病毒感染所引起，所以短期使用糖皮质激素(泼尼松1 mg/kg·日，1-2周后减量并停用)可有效治疗扁桃体的过度增生或自身免疫症状。另外，糖皮质激素还可用于治疗传染性单核细胞增多症相关的其它罕见的自身免疫反应并发症，如中枢神经系统受累、心肌炎或心包炎(49)等。在这种情况下，除非存在药物禁忌症，我们通常在使用糖皮质激素的同时联合应用阿昔洛韦。

Splenic rupture is a rare but potentially fatal complication of infectious mononucleosis and occurs in approximately 0.1% of cases of infectious mononucleosis (4, 20). Splenic rupture is more common in males and approximately half the cases are spontaneous (not associated with trauma or other contributory factors). In one review of 55 cases of infectious mononucleosis-associated splenic rupture, all cases occurred within three weeks after the beginning of illness. Another case-control study which combined physical, ultrasound and laboratory examinations of infectious mononucleosis patients found that physical examination was an insensitive method of detecting splenomegaly (17%), but all patients were found to have splenomegaly for the first 20 days, and the severity of laboratory abnormalities did not correlate with splenic enlargement (17). Although various strategies to minimize the risk of splenic rupture have been advanced, incorporating the results of physical exam and ultrasound imaging, no studies have validated the utility of such approaches. It therefore seems prudent to recommend avoidance of contact sports or activities that raise intra-abdominal pressure such as weight lifting for a minimum of four weeks after the onset of illness.

脾破裂在发生率在传染性单核细胞增多症中为0.1%，虽然罕见，但可以导致死亡(4, 20)。并发脾破裂者男性多见，一半为自发性，与外伤等因素无关。一篇综述报告的55例传染性单核细胞增多症合并的脾破裂病例全部发生于起病后3周之内。另一篇病例对照研究则综合运用体格检查、超声和实验室检查三种方法用于检测传染性单核细胞增多症病人脾脏肿大，发现所有患者在发病20天内均有脾脏肿大；体格检查发现脾脏肿大的敏感性差，仅为17%；实验室检查结果的异常的严重程度与脾脏肿大的程度无关(17)。结合体格检查和超声波检查的结果，人们采用了多种方法以减少脾破裂的危险，但并未发现其有效。所以应建议病人在发病四周内避免对抗性强或如举重等增加腹压的体育活动。

Patients recovering from infectious mononucleosis may shed virus in saliva for periods of several months after recovery despite being clinically well (See Epidemiology above). Furthermore, it is clear that all latently infected humans may intermittently shed EBV in saliva. It is therefore difficult for seronegative subjects to avoid the risk of acquiring EBV infection. It appears that intimate sexual contact is more likely to transmit EBV infection.

传染性单核细胞增多症恢复期的患者在症状消失后数月内，唾液中仍可存在脱落的病毒；所有潜伏感染患者的唾液中可间断出现脱落的病毒颗粒，所以血清学阴性个体也能为EB病毒获得性感染的传染源，亲密的性接触更容易造成EB病毒感染传播。

If possible, the treatment of choice is to reduce the level of immunosuppression (82). However, in hematopoietic stem cell transplantation, this is rarely possible since patients have received immune-ablative therapy. Anti-B lymphocyte monoclonal antibodies specific for the B cell antigen CD20 (rituximab) are commonly used as therapy for imminent or active PTLD (46). Although impressive success rates in excess of 70% have been reported, the long term effects of profound global B cell depletion are unknown. Recently, investigators have successfully treated EBV-induced lymphoproliferative disease by augmenting the host’s immune response through adoptive transfer of EBV-specific cytotoxic T cells grown in vitro (72, 73, 74). In PTLD arising in the setting of hematopoietic stem cell transplantation, the donor’s T cells are harvested prior to transplantation and stimulated in vitro with an EBV-infected B cell line which can also be generated from the donor. Cytotoxic T cells specific for EBV antigens are stimulated and expanded in vitro. After transplantation, patients are monitored for EBV viral load by polymerase chain reaction for viral DNA in peripheral blood lymphocytes. If the viral load begins to increase beyond acceptable levels or if EBV-infected tumors are detected, the EBV-specific cytotoxic T lymphocytes are infused. These cytotoxic T lymphocytes amplify in vivo and persist long-term. Adoptive transfer of EBV-specific cytotoxic T lymphocytes has been shown to reduce the incidence of EBV-associated lymphoproliferative disease and to induce regression of established EBV-infected lymphoproliferations (34, 76). Complications due to the inflammatory response associated with cytotoxic T lymphocyte treatment in sensitive anatomic locations such as the airway or gastrointestinal tract have been observed. In addition, tumors infected with escape mutants of EBV that are not recognized by the epitope-specific cytotoxic T lymphocytes have also arisen (22). The risk for such mutants is particularly high where the tumor burden is large. Infusion of EBV-specific cytotoxic T lymphocytes, although an attractive form of specific therapy, requires two to three months and the expertise in cytotoxic T lymphocytes generation.

若条件允许，应选择降低免疫抑制的程度(82)。但造血干细胞移植的病人已接受了免疫去除治疗，鲜有降低免疫抑制的可能。抗B淋巴细胞抗原CD20的单克隆抗体(利妥昔)已被广泛用于治疗危重或活动性移植后淋巴细胞增殖性疾病(PTLD) (46)。虽有报道其成功率超过70%，但机体去除B细胞后长期的影响尚不明确。最近有研究者通过将体外培养的EB病毒特异细胞毒性T细胞输入病人体内，以增强其免疫反应，治疗EB病毒诱导的淋巴细胞增殖性疾病取得成功(72, 73, 74)。在开展造血干细胞移植机构，PTLD发病率不断增高，可以在移植前采集供者的T细胞并且在体外用同样从供者采集的EB病毒感染B细胞进行刺激，这样EB病毒抗原特异性的细胞毒性T细胞在体外被刺激产生并增殖。移植后，用PCR方法监测病人外周血中病毒DNA的定量，一旦发现病毒量超过可接受范围或发现EB病毒感染相关肿瘤，就给病人输注事先制备好的EB病毒特异性细胞毒T淋巴细胞。这些细胞毒性T细胞可在病人体内增殖且长期存在。这种方法可减少EB病毒相关淋巴细胞增殖性疾病的发病和逆转已出现的EB病毒感染引起的淋巴细胞增殖性疾病(34, 76)。据报道这种治疗的主要并发症是可在如气道及消化道等某些敏感的解剖学部位诱发炎症反应；此外， EB病毒的变异株可以发生抗原改变，逃逸特异表型的细胞毒性T细胞的识别，由这些变异EB病毒感染相关肿瘤的发病率在增加(22)。在肿瘤负荷大的病人中尤其容易出现EB病毒的变异；尽管输注EB病毒特异细胞毒性T细胞是一种非常好的特异治疗手段，但其制备需要2-3月的时间，并且需要掌握细胞毒性T细胞的传代的专业人员。

In patients with solid organ transplants, reduction in immunosuppression is ideal but often carries the risk of endangering graft and/or patient survival. Adjunctive therapy, including interferon, IL-6, and cytotoxic T lymphocytes have been used, but must be considered unproven therapy although favorable results have been reported. As in the case of hematopoietic stem cell transplantation, rituximab has been used with varying degrees of success.

对于实体器官移植患者，最理想的是能降低其免疫抑制程度，但通常会增加移植排异的危险，甚至危及生命。虽有病例报道，应用干扰素、白介素-6 (IL-6)及细胞毒性T细胞等辅助治疗有效，但尚未经普遍证实。造血干细胞移植病人应用（利妥昔单抗）取得不同程度疗效。

Hematopoietic stem cell transplantation performed during childhood with HLA-identical sibling donors, regardless of EBV serologic status, offers potentially curative therapy for X-linked lymphoproliferative disease (25).

无论EB病毒血清学是否阳性，儿童时期接受相同HLA同胞提供的造血干细胞移植是可能根治X-连锁淋巴增殖性疾病(25)。

EBV-Associated Malignancies (Burkitt’s Lymphoma, Nasopharyngeal Carcinoma, Hodgkin’s lymphoma)

EB病毒相关恶性肿瘤(Burkitt’s 淋巴瘤,鼻咽癌,霍奇金淋巴瘤)

The usual treatment for EBV-associated malignancies is based on cancer chemotherapy and radiation therapy as opposed to antiviral strategies. As mentioned above, the progression of some of these malignancies can be extremely rapid and referral to a specialized oncology center is essential for prompt diagnosis, staging, and appropriate initial therapy.

EB病毒相关恶性肿瘤常规治疗以肿瘤化疗和放疗为主，而非抗病毒治疗。之前已提到，这些肿瘤可进展迅速，应转诊到肿瘤中心尽快确诊、分期并开始正规治疗。

Potential strategies for EBV vaccination include prophylactic approaches (to prevent infection or attenuate morbidity associated with primary infection/infectious mononucleosis), post-infection approaches (to reduce or eliminate persistent EBV infection and risk of EBV-associated malignancies), and therapeutic approaches (to treat established EBV-infected malignancies). Most work has focused on the EBV major membrane glycoprotein, gp350, as a potential EBV vaccine (54). EBV binding to the cellular receptor, CD21, is mediated by gp350 (57), and a gp350 subunit vaccine can prevent the development of lymphomas after injection of EBV in a cotton-top tamarin animal model for EBV infection (52, 53, 67). A small trial with a recombinant gp350 vaccinia virus vaccine showed that it can induce EBV neutralizing antibodies in human volunteers. However, 3/9 vaccinated volunteers with neutralizing antibody were subsequently infected with EBV by natural routes of transmission (26). A recently completed phase II trial showed that the EBV gp350 subunit vaccine was associated with a decreased risk of infectious mononucleosis in a cohort of students. More studies will be required to determine the role of humoral versus cellular immunity, the importance of mucosal immunity, the optimal adjuvant and delivery system for gp350 vaccines, and whether a gp350 vaccine will decrease the increased risk of malignancy associated with EBV infection. In this regard, attenuation rather than prevention of infectious mononucleosis by the vaccine may be sufficient to decrease the risk of malignancy associated with severe primary infection. It remains to be shown whether gp350 represents the optimal candidate for an EBV vaccine. Vaccines that induce cytotoxic T cell activity against EBV latent genes have also been proposed as a potentially effective vaccine strategy. Preliminary trials in volunteers using synthetic peptides of multiple fused EBV cytotoxic T lymphocyte epitopes are also underway (44). An animal model in rhesus monkeys that reproduces the natural route of oral transmission and other aspects of acute and persistent EBV infection has recently been established and the complete sequence of the rhesus EBV homolog has been determined (51, 71). These advances should be useful for the development of effective EBV vaccine strategies.

研发EB病毒疫苗包括预防性疫苗(用以预防感染或降低原发感染或传染性单核细胞增多症发病率)，感染后控制病情疫苗(减少或消除EB病毒持续感染和EB病毒感染引发的恶性肿瘤)及治疗疫苗(治疗EB病毒感染引发的恶性肿瘤)。多数疫苗研究工作集中在EB病毒主要膜糖蛋白——gp350(54)。EB病毒通过gp350与细胞膜受体CD21结合(57)，在EB病毒感染的动物模型中进行的实验发现，gp350亚基疫苗可防止淋巴瘤发生(52, 53, 67)。一项在健康受试者中进行的小型临床实验发现，接种重组gp350牛痘病毒疫苗可诱导其产生EB病毒中和抗体，但后来9名接种疫苗的健康受试者中3名自然感染了EB病毒(26)。最近已完成的一项II期临床实验发现EB病毒gp350亚基疫苗和参加研究的学生人群肿传染性单核细胞增多症的发病减少有关。但有关gp350疫苗的许多方面尚需进行更多的研究，如体液免疫与细胞免疫的作用、粘膜局部免疫的重要性、最佳佐剂和接种方法以及其是否能够由EB病毒感染引发的恶性肿瘤发生风险等。由此看来，无需预防疫苗，可能仅通过疫苗减轻传染性单核细胞增多症的病情就可有效降低由严重原发感染引发的恶性肿瘤。同时关于gp350是否试EB病毒疫苗的最佳选择仍需进一步研究。此外，旨在诱导产生针对EB病毒潜伏基因的细胞毒性T细胞的疫苗可能是一个研究方向。目前正在志愿者中进行包含多个EB病毒特异细胞毒性T细胞表位的人工合成多肽疫苗的初步临床实验(44)。最近在建立的恒河猴动物模型中，已能使其成功经口腔自然途径感染EB病毒，产生急性和持续性EB病毒感染的，并已完成其潜伏感染后全部基因测序。上述进展有利于EB病毒有效疫苗的研发。

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