Chronic active Epstein–Barr virus infection with intrapulmonary shunting: A case report

Chronic active Epstein–Barr virus (EBV) infection (CAEBV) is a high-mortality form of EBV infection. However, chronic hypoxemia is rare in these patients. We herein reported a case of severe hypoxemia due to intrapulmonary shunting in CAEBV. A 17-year-old girl presented with fever, dyspnea, cyanosis, and hepatosplenomegaly. Laboratory tests showed mild liver dysfunction and high copy numbers of EBV-DNA in the peripheral blood. A left supratrochlear lymph node biopsy showed infiltration of highly proliferative T lymphocytes with positive EBV encoded small RNA by in situ hybridization. Technetium-99m-labeled macroaggregated albumin and contrast-enhanced echocardiography confirmed the existence of intrapulmonary shunting, which was probably related to hepatopulmonary syndrome. The final diagnosis was CAEBV with intrapulmonary shunting. The patient was treated with cyclosporine A, etoposide, and dexamethasone. Finally, the patient died of respiratory failure. Intrapulmonary shunting is a rare complication of CAEBV. Early recognition and exploring the cause of hypoxemia should be highlighted in patients with CAEBV.     

儿童Epstein—Barr病毒感染临床分析

目的探讨慢性活动性Epstein—Barr病毒（EpsteinBarrvirus,EBV）感染、急性EBV感染及正常儿童EBV—DNA及适应性体液免疫的差异。方法慢性活动性EBV感染患儿8例（慢性组）,急性EBV感染患儿13例（急性组）,正常儿童12例（对照组）外周血单个核细胞采用实时荧光定量PCR法检测,3组EBV—DNA水平,采用ELISA、抗体稀释试验评价EBV适应性体液免疫,分析其与EBV感染不同转归的关系。结果慢性组EBV—DNA载量、病毒壳蛋白抗原-IgA、-IgG及早期抗原-IgA水平明显高于急性组和对照组（P〈0．01）,病毒壳蛋白抗原-IgM水平及早期抗原-IgG滴度改变速率低于急性组（P〈O．01）;慢性组与急性组EBV核抗原-IgG抗体水平均低于对照组（P〈0．01）。结论慢性活动性EBV感染存在不同EBV核抗原-LP拷贝数及不同亲和力的抗体谱,可能与慢性活动性病程相关,对早期识别诊治有重要意义。     

慢性活动性EB病毒感染的研究进展

机体感染EB病毒(EBV)后,可以表现为持续性或反复发作性发热,肝、脾、淋巴结大,以及肝丙氨酸氨基转移酶水平异常增高等传染性单核细胞增多症(IM)样症状.伴随EBV特异性抗体谱表达与外周血EBV-DNA拷贝数显著增高的EBV感染,称为慢性活动性EB病毒感染(CAEBV).CAEBV为一种临床少见的致命性疾病,预后凶险,导致的患者病死率极高.目前,CAEBV的发病机制尚未完全阐明,亦无标准治疗方案.笔者拟就CAEBV的发病机制、临床表现、诊断及治疗研究的最新进展进行综述,旨在提高临床医师对CAEBV的认识.     

Quantification of epstein-barr virus DNA is helpful for evaluation of chronic active epstein-barr virus infection

Chronic active Epstein-Barr virus infection (CAEBV) presents with chronic or recurrent infectious mononucleosis-like symptoms, such as low-grade fever, liver dysfunction, lymphadenopathy, and hepatosplenomegaly. Immunological methods are useful for the diagnosis of viral infections. However, CAEBV patients do not necessarily have high titers of Epstein-Barr virus (EBV)-specific antibodies. Hosts that are immunocompromised after hematopoietic stem cell transplantations sometimes suffer from systemic EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and EBV-positive lymphoma. Patients with EBV-associated diseases are often diagnosed by analyses of bone marrow. Cytomegalovirus (CMV) can cause serious pneumonia or retinitis in immunocompromised hosts. In order to noninvasively understand the clinical status of patients with EBV-associated diseases, we conducted real-time polymerase chain reaction (PCR) methods in their peripheral blood in order to quantify EBV and CMV DNA levels, which reflect viral activity. Here, we describe a 30-year-old Japanese female patient with CAEBV. The patient had repeated fever, fatigue, and liver dysfunction. The histopathological results of liver biopsies were positive for EBV-encoded RNA-1. Acute hepatitis was associated with the EBV infection. The whole-blood EBV DNA levels were high and above 1.0 × 10⁷ copies/mL. After immunosuppressive and antiviral therapies, EBV DNA levels lowered. However, she had to receive bone marrow transplantation because of her EBV-HLH. As the number of lymphocytes increased in the post-transplantation period, EBV DNA levels gradually increased again. The simultaneous detection of CMV DNA was more sensitive than the CMV antigenemia test that is often used to diagnose CMV infections. Unfortunately, the patient died due to a fungal infection. Observing EBV DNA levels closely with real-time quantitative PCR methods is helpful for evaluating the changes in the clinical course.     

CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA.

Lymphoproliferative disease of granular lymphocytes (LDGL) is a heterogeneous disorder and the pathogenesis is likely to be complex. Some patients with chronic active EBV (CAEBV) infection also have LDGL. To investigate the relationship between EBV infection and the pathogenesis of LDGL, we conducted a survey for EBV DNA sequences by Southern blot analysis of DNA obtained from the peripheral blood of seven patients with LDGL, including one with CAEBV infection. Interestingly, EBV DNA was detected in the sample from the patient with CAEBV infection, and in the samples from four other patients with CD3-LDGL. Moreover, a single band for the joined termini of the EBV genome was demonstrated in two samples, suggesting a clonal disorder of those LDGL. These findings strongly suggest that EBV may play a pathogenic role in some cases of LDGL.     

An adult-onset case of chronic active Epstein-Barr virus infection with fulminant clinical course

A 56-year-old Japanese male with chronic active Epstein-Barr virus (EBV) infection (CAEBV) who developed systemic gamma-delta T-cell lymphoproliferative disease (LPD) is reported. Although immune cooling therapy was effective, he died of sudden and severe hypoxia and anemia soon after the initiation of cytotoxic chemotherapy that had been previously recommended. There might remain a difficulty to control fulminant adult-onset CAEBV. Additionally, we describe three types of lymphoid cells that were observed in his peripheral blood: morphologically normal lymphocytes, large blastic cells and mature ones with rough granules. Morphological observation appeared to be useful to estimate clinical manifestations. Since CAEBV is extremely rare disease in adult population, it is important to accumulate clinical data to more understand the pathogenesis or to establish treatment strategy.     

儿童慢性活动性EB病毒感染的相关血液疾病特征

本研究通过4个病例分析儿童慢性活动性EB病毒（CAEBV）感染相关的血液学病征。总结了临床特点，应用显微镜观察骨髓涂片的细胞形态，流式细胞仪分析淋巴细胞亚群，免疫组织化学检测肝穿刺组织，酶联免疫吸附试验（ELISA）检测血浆EBV抗体，实时定量PCR检测血浆EBV—DNA，原位杂交检测外周血单个核细胞（PBMNCs）EBV编码小RNA-1（EBER-1）。结果显示：4例患儿有持续或反复的发热、肝脾肿大、肝功能异常、贫血、血小板减少症、全身炎症反应；骨髓象表现增生减低、成熟障碍、病态造血和噬血细胞增多；4例患者均有CD8^＋T淋巴细胞增多，其中1例进展为T细胞淋巴瘤；2例EBV—VCA-IgG滴度≥1：5120，1例血浆EBV-DNA拷贝数为3．26×10^3／ml，1例PBMNC的EBER1阳性率为1．7％；最后，4例患者均被诊断为CAEBV。结论：免疫相关性血细胞减少、巨噬细胞活化综合征和淋巴细胞增殖性疾病等是本研究中4例CAEBV患儿的血液学病征。     

慢性活动性EB病毒感染临床分析

目的通过总结、分析慢性活动性EB病毒感染（CAEBV）患者的临床资料,以提高对CAEBV的诊断、治疗的认识。方法回顾性分析2008年10月-2013年1月诊治的9例CAEBV患者的临床症状特点,以及实验室检食、病原学相关检查、影像学和病理学检佥结果等,并评估其对药物治疗的反应和随访、预后表现。结果CAEBV临床症状缺乏特异性,主要表现为发热、肝脾和淋巴结肿大,其他尚有乏力、恶心、皮疹、黄疸等。辅助检查的异常发现包括：贫血、白细胞降低、中性粒细胞降低、血小板减少、乳酸脱氧酶及羟丁酸脱氢酶升高等肝功能异常及胸部影像学的异常表现等。病原学相关检查结果：6例患者抗EB病毒衣壳抗原IgA抗体升高,8例EB病毒早期抗原IgG为阳性,实时定量聚合酶链反应俭测外周血EB病毒DNA载量（中位数）为3．07×10^5copies／mL。9例患者中6例死亡,其中1例死于颅内出血,1例死于多脏器功能衰竭,1例死于噬血细胞综合征,1例死于肺部感染4例患者进展为淋巴瘤,在抗肿瘤治疗过程中1例死于肝功能衰竭,1例死于严重感染。结论CAEBV临床表现多样且缺乏特异性,常伴有各系统严重并发症,部分患者可进展为淋巴细胞增殖性疾病,预后差,病死率高,应引起临床重视。     

Evaluation of antibodies to the Epstein-Barr virus immediate early gene product ZEBRA by a new enzyme-linked immunosorbent assay.

For the serodiagnosis of Epstein-Barr virus (EBV) infections, we have developed a new enzyme-linked immunosorbent assay (ELISA) for antibodies to the ZEBRA product of EBV immediate early gene BZLF1. ZEBRA protein fused with glutathione-S-transferase (GST) was expressed in Escherichia coli and purified by affinity chromatography with glutathione-Sepharose 4B. An ELISA sandwich capture system was constructed with the GST-ZEBRA immobilized on plastic microtiter plates which had been coated with a mouse monoclonal antibody to GST. ZEBRA-IgG antibodies in patients' sera with chronic active EBV infection (CAEBV) and infectious mononucleosis (IM) had, respectively, very high and high titers. Anti-ZEBRA antibodies were also detected at low titers in sera of some healthy controls. ZEBRA-IgM antibodies were detected in sera of patients with IM and CAEBV but not in sera of healthy controls. In sera of patients with CAEBV, the titers of IgG antibodies to ZEBRA correlated with the antibody titers to early antigens obtained with an immunofluorescence assay, but not to EBV nuclear antigens. This ELISA is a useful diagnostic and prognostic test for EBV infection.     

荧光定量PCR检测儿童非典型EB病毒感染的临床评价

目的探讨荧光定量PCR检测对诊断和治疗非典型EB病毒(EBV)感染的临床意义。方法对2007-04-2009-10诊断为非典型EBV感染90例患儿,抽静脉血2 ml,注入枸橼酸钠抗凝剂与静脉血充分混匀,用核酸扩增荧光PCR法测定基因拷贝数,同时进行常规外周血及异型淋巴细胞检查,对照病因和首发临床表现,分析儿童感染非典型EBV时荧光定量PCR检测的基因拷贝数变化。结果 EBV-DNA拷贝数能早期反映出非典型EBV感染,拷贝数越高,出现多器官损害概率越高。结论荧光定量PCR检测EBV-DNA拷贝数有助于早期诊断非典型EBV感染,能减少诊疗的盲目性,对临床有一定指导意义。     

Negative conversion of autoantibody profile in chronic hepatitis B: A case report

BACKGROUNDAutoimmune antibodies are detected in many diseases. Viral infections are accompanied by several immunopathological manifestations. Some autoimmune antibodies have been associated with the immune response induced by virus or drugs. Thus, a comprehensive diagnosis of chronic hepatitis B combined with autoimmune hepatitis is required, and immunosuppressant or antiviral therapy should be carefully considered.CASE SUMMARYWe present a case of a patient who had negative transformation of autoimmune antibodies during chronic active hepatitis B. A 50-year-old female who had a history of asymptomatic hepatitis B virus carriers for more than 10 years presented to the hospital with the complaint of weakness for 1 wk. Blood tests revealed elevated liver enzymes; the detection of autoantibodies was positive. Hepatitis B viral load was 72100000 IU/mL. The patient started tenofovir alafenamide fumigate 25 mg daily. Liver biopsy was performed, which was consistent with chronic active hepatitis B. The final diagnosis of the case was chronic active hepatitis B. The autoimmune antibodies turned negative after 4 wk of antiviral therapy. The patient recovered and was discharged with normal liver function. There was no appearance of autoantibodies, and liver function was normal at regular follow-ups.CONCLUSIONAutoimmune antibodies may appear in patients with chronic active hepatitis. It is necessary to differentiate the diagnosis with autoimmune hepatitis.     

荧光定量聚合酶链反应法检测咽拭子EBV—DNA在早期诊断EBV感染中的作用

目的 探讨咽拭子荧光定量聚合酶链反应（FQ-PCR）法检测非洲淋巴细胞瘤病毒脱氧核糖核（EBV—DNA）在早期诊断EBV感染中的应用价值。方法对于疑诊EBV感染的患儿在疾病初期分别采用咽拭子PCR法检测EBV—DNA,同时用酶联免疫吸附测定（ELISA）法检测静脉血EBV—VCA—IgM和（或）IgG,对于前者阳性而后者阴性的病例在1周后复查EBV—VCAIgM和IgG,比较两者在早期诊断EBV感染中的价值。同期检测健康儿童50例作为对照组。结果①共检测疑诊病例985例,其中EBV—DNA阳性344例,阳性率34．9％,EBV—VCA—IgM和（或）IgG阳性164例,阳性率16．6％;健康对照组检测50例,仅1例EBVDNA阳性,所有病例EBV—VCA—IgM和（或）IgG均阴性。②在纳入研究病例中,诊断为传染性单核细胞增多症者38例,其中EBV—DNA37例阳性、EBV—VCAIgM和（或）IgG27例阳性（P〈0．05）。诊断为非典型EBV感染的312例,其中EBVDNA阳性307例,阳性率98．4％,EBV—VCA—IgM和（或）IgG阳性137例,阳性率43．9％（P〈0．01）。结论咽拭子PCR法检测EBV—DNA敏感度高,特异度强,且取材简单,方法无创,家长易于接受,与检测EBV-VCA—IgM、IgG相比,在早期诊断EBV感染性疾病,尤其是非典型EBV感染很有应用价值。     

Detection of Epstein-Barr virus in breast carcinoma in Egyptian women

BackgroundThe association of oncogenic EBV with breast carcinoma (BC) is still in controversy.Aim of workAssess the association of EBV with BC in Egyptian women and find possible relationship between prognostic factors of BC and EBV detection.Subjects and methodsParaffin-embedded sections from 40 female patients with primary invasive BC; ductal (n = 32) and lobular (n = 8) and breast tissues from patients with fibrocystic disease (n = 20) as control were screened for presence of EBV by EBV nuclear antigen-1 (EBNA-1) immunostaining and by PCR for EBV-DNA.Results10 / 40 (25%) of the BC specimens stained positively for EBNA-1; EBNA-1 expression was restricted to a fraction 5%–60% of tumor epithelial cells. EBV-DNA was detected in 8 / 10 of BC specimens positive for EBNA-1. Control specimens were negative by both techniques. 7 / 8 (87.5%) of EBV-DNA positive tumors were associated with > 3 lymph nodes involvement.ConclusionEBV is associated with some invasive BC in Egyptian females and may play a role in their etiology.     

Chronic mononucleosis syndrome

We present data on 14 patients with chronic symptoms of disabling fatigue in association with serologic evidence of active Epstein-Barr virus (EBV) infection. Two thirds were women, and the average age at onset was 29.6 years. Forty-three percent were known to have had previous infectious mononucleosis, but the usual criteria for that diagnosis were not helpful with the present syndrome. Eighty-six percent had serologic evidence of cytomegalovirus (CMV) infection. Profound immunodeficiency was not present, but 71% had partial hypogammaglobulinemia, and minor abnormalities of T cell subsets were noted in six of seven patients studied. Fifty-seven percent achieved temporary serologic and symptomatic remission after an average duration of 33 months. Only one patient has a sustained remission. Comparison is made with other reported chronic, recurrent, and persistent EBV syndromes, and tentative diagnostic criteria for chronic mononucleosis syndrome are presented. Recently available EBV serologic techniques allow for identification of patients who have reactivated EBV infection, and this reactivation may be related to symptoms.     

浙江地区胃癌与EB病毒感染的相关性研究

目的 调查浙江地区胃癌病人胃组织中EB病毒的感染情况。方法 用PCR方法对26例胃癌组织和15例非胃癌胃组织标本进行EBV -DNA测定。 结果 26例胃癌病人胃癌组织EBV -DNA阳性19例 (73.1 % ) ;其中9例分化型腺癌EBV -DNA阳性5(55.6 % ) ,12例低分化腺癌阳性11例 (91.7 % ) ;5例粘液、印戒细胞癌阳性3例 (60 % )。对照组15例胃组织阳性6例 (40% ) ,( χ2=4.37,p<0.05)。结论 本研究提示 ,浙江地区胃癌病人胃癌组织存在较高的EB病毒感染 ,EB病毒可能参与了胃癌的发生     

基于ddPCR技术分析EB病毒载量特征及与qPCR技术的比较研究

目的解决临床工作中应用实时荧光定量PCR(qPCR)方法检测EB病毒(EBV)载量与临床诊断不符的问题,探讨微滴式数字PCR(ddPCR)和qPCR方法检测EBV载量的能力并为临床提供可能的解决方案。方法收集510例疑似EBV感染相关疾病患者血浆标本,采用ddPCR和qPCR两种方法测定同一血浆标本的EBV-DNA载量。结果 EBV感染人群中,EBV-DNA载量较其他地区低,载量中位数仅360copies/mL,其中初诊未治鼻咽癌患者中位病毒载量为4 590copies/mL,治疗后鼻咽癌患者中位病毒载量下降为430copies/mL,免疫力低下者中位病毒载量为130copies/mL,而淋巴瘤患者中位病毒载量为840copies/mL;qPCR检测EBV感染以400copies/mL为界值,高于400copies/mL时,ddPCR与qPCR的EBV-DNA测定水平值呈中度相关(r=0.533,P<0.05),低于400copies/mL时,ddPCR与qPCR的EBV-DNA测定水平值呈弱相关(r=0.299 5,P<0.05);以ddPCR为标准,qPCR检测EBV-DNA的灵敏度仅为0.317,以ddPCR检测结果为标准,构建qPCR的受试者工作特征曲线下面积为0.871,此时临界值(qPCR)为10copies/mL,灵敏度为0.824,特异度为0.780。结论采用ddPCR方法或优化qPCR的临界值去检测EBV-DNA载量更能为临床诊断EBV感染提供有利支持。     

Successful treatment of infantile hepatitis B with lamivudine: A case report

BACKGROUNDHow to treat infantile hepatitis B virus (HBV) infection remains a controversial issue. The nucleoside analogue lamivudine (LAM) has been approved to treat children (2 to 17 years old) with chronic hepatitis B. Here, we aimed to investigate the benefit of LAM treatment in infantile hepatitis B.CASE SUMMARYA 4-mo-old infant born to a hepatitis B surface antigen (HBsAg)-positive woman was found to be infected by HBV during a health checkup. Liver chemistry and HBV seromarker tests showed alanine aminotransferase of 106 U/L, HBsAg of 685.2 cut-off index, hepatitis B “e” antigen of 1454.0 cut-off index, and HBV DNA of > 1.0 × 10⁹ IU/mL. LAM treatment (20 mg/d) was initiated, and after 19 mo, serum HBsAg was entirely cleared and hepatitis B surface antibody was present. The patient received LAM treatment for 2 years in total and has been followed for 3 years. During this period, serum hepatitis B surface antibody has been persistently positive, and serum HBV DNA was undetectable.CONCLUSIONEarly treatment of infantile hepatitis B with LAM could be safe and effective.     

Chronic active Epstein-Bar virus infection complicated by pulmonary artery hypertension

Chronic active Epstein-Bar virus infection (CAEBV) is known to cause various symptoms. Although pulmonary artery hypertension (PAH) has been reported as a cardiovascular complication of CAEBV, the mechanisms of PAH and the effects of treatment have not been fully elucidated.We experienced 4 adult patients with CAEBV complicated by PAH. All of them received treatment for PAH with a vasodilator followed by chemotherapy with or without allogeneic hematopoietic cell transplantation for CAEBV. In all of these patients, the transtricuspid pressure gradient improved under treatment with vasodilator, and further improvement was observed under treatment for CAEBV in 3 patients. Autopsy was performed in 2 patients, which revealed EBER-positive cells and a change in the pulmonary artery at each stage in the pathology. In conclusion, EBV-infected cells can cause vasculitis and finally PAH. However, PAH complicated with CAEBV can be improved by PAH medication and treatment of CAEBV.     

Postoperative pain due to an occult spinal infection: A case report

BACKGROUNDA high degree of vigilance is warranted for a spinal infection, particularly in a patient who has undergone an invasive procedure such as a spinal injection. The average delay in diagnosing a spinal infection is 2-4 mo. In our patient, the diagnosis of a spinal infection was delayed by 1.5 mo.CASE SUMMARYA 60-year-old male patient with a 1-year history of right-sided lumbar radicular pain failed conservative treatment. Six weeks to prior to surgery he received a spinal injection, which was followed by increasing lumbar radicular pain, weight loss and chills. This went unnoticed and surgery took place with right-sided L4-L5 combined microdiscectomy and foraminotomy via a posterior approach. The day after surgery, the patient developed left-sided lumbar radicular pain. Blood cultures grew Staphylococcus aureus (S. aureus). Magnetic resonance imaging showed inflammatory aberrations, revealing septic arthritis of the left-sided L4/L5 facet joint as the probable cause. Revision surgery took place and S. aureus was isolated from bacteriological samples. The patient received postoperative antibiotic treatment, which completely eradicated the infection.CONCLUSIONThe development of postoperative lower back pain and/or lumbar radicular pain can be a sign of a spinal infection. A thorough clinical and laboratory work-up is essential in the preoperative evaluation of patients with spinal pain.