Primary Epstein-Barr Virus Research Articles

Epstein-Barr virus hepatitis associated withicterus: A case report

Primary Epstein-Barr virus infection (EBVI) in children is usually asymptomatic with seroconversion. If primary infection occurs in adolescents or in adulthood, the most common manifestation is acute infectious mononucleosis. The diagnosis of acute infectious mononucleosis is made by virus and serologic tests. The most important evidence of primary EBV infection includes IgM class antibodies detected by using EBV virus-capsid-antigen (EBV VCA) which appears at the beginning of illness and usually lasts 1 to 2 months. Paul Bunnell Davidson test, although non-specific, is still in use today in diagnosis of infectious mononucleosis and for detection of heterophile antibodies. Acute hepatitis with icterus is a rare clinical manifestation in primary EBV infection. However, sometimes it is the only manifestation of the disease. This is a case report of a patient with EBV hepatitis and icterus associated with long-lasting fever without pharyngitis and lymphadenopathy, which are characteristics of infectious mononucleosis. The etiologic diagnosis was confirmed by positive Paul Bunnell Davidson test and by detection of specific antibodies (class IgM) to EBV VCA in patient's serum. The pathogenetic mechanism which causes destruction of hepatic cells and provokes cholestasis during EBV infection, has not been cleared yet. It is supposed that EBV has no direct cytocide effects on hepatic cells, yet destruction of these cells is caused by toxic action of free radicals through lipid peroxidation. Patients with infectious mononucleosis have autoantibodies directed against enzyme superoxide-dismutase which neutralizes enzyme's antioxidant action. As a result of this action, free radicals accumulate in hepatic cells and cause their damage. Icteric forms of EBV infection are rare. In differential diagnosis of icterus caused by infectious agents, one should not forget EBV.

Multiple Epstein‐Barr Virus Strains in Patients with Infectious Mononucleosis: Comparison of Ex Vivo Samples with In Vitro Isolates by Use of Heteroduplex Tracking Assays

Recent work using a heteroduplex tracking assay (HTA) to identify resident viral sequences has suggested that patients with infectious mononucleosis (IM) who are undergoing primary Epstein-Barr virus (EBV) infection frequently harbor different EBV strains. Here, we examine samples from patients with IM by use of a new Epstein-Barr nuclear antigen 2 HTA alongside the established latent membrane protein 1 HTA. Coresident allelic sequences were detected in ex vivo blood and throat wash samples from 13 of 14 patients with IM; most patients carried 2 or more type 1 strains, 1 patient carried 2 type 2 strains, and 1 patient carried both virus types. In contrast, coresident strains were detected in only 2 of 14 patients by in vitro B cell transformation, despite screening >20 isolates/patient. We infer that coacquisition of multiple strains is common in patients with IM, although only 1 strain tends to be rescued in vitro; whether nonrescued strains are present in low abundance or are transformation defective remains to be determined.

Real-Time Epstein-Barr Virus PCR for the Diagnosis of Primary EBV Infections and EBV Reactivation

The serological diagnosis of primary Epstein-Barr virus (EBV) infections is often difficult, whereas the relevance of elevated immunoglobulin G (IgG) antibodies against early antigen (EA) for the diagnosis of EBV reactivation has increasingly become a matter of dispute. Recently, EBV PCR has been added as a diagnostic tool. Positive EBV PCR has been demonstrated in the serum of patients with primary EBV infections and EBV reactivation. To compare classical serological diagnosis of primary EBV infection and EBV reactivation with real-time EBV PCR. Sera from 45 patients were selected with detectable immunoglobulin M (IgM) antibodies against EBV viral capsid antigen (VCA), and 62 sera were selected with a reactivation profile. A real-time EBV PCR was performed with DNA extracted from these sera. Based on serological data, the diagnosis of primary EBV infection was established for 24 of the 45 IgM VCA-positive patients. By performing PCR, seven extra cases of primary infection were diagnosed for which no heterophilic antibodies could be detected. In five cases of primary infection, no EBV DNA could be detected by PCR. Only in two of the 62 sera with a reactivation seroprofile could EBV DNA be detected. Based on these data, we suggest that for the diagnosis of primary infections, EBV PCR could lead to an increase of >16% in the number of positive diagnoses by confirming a positive IgM VCA in the absence of heterophilic antibodies. Furthermore, EBV PCR is positive in only 3% of sera with elevated antibodies against EA, raising doubt as to the utility of EA titers for diagnosing EBV reactivation.

Acute reversible parkinsonism in Epstein–Bbarr virus–related encephalitis lethargica‐like illness

A 10-year-old boy presented with fever, headache, vomiting, and hypersomnolence. An akinetic-rigid syndrome with tremor, dysphagia, dysphonia, and sialorrhea, as well as pyramidal signs, developed. Slightly elevated protein content was found in the cerebrospinal fluid and serological investigations were suggestive of a primary Epstein-Barr virus infection. Magnetic resonance imaging (MRI) showed massive bilateral hyperintense striatal and punctiform periventricular lesions. After 2-month treatment with steroids and antiparkinsonian drugs, all features resolved without sequelae. Control MRI demonstrated only minimal residual lesions in both putamina. Strongly resembling the encephalitis lethargica-like syndrome, this case is an unusual presentation of parainfectious acute disseminated encephalitis.

Association of virus infected-T cell in severe hepatitis caused by primary Epstein-Barr virus infection

Background Infectious mononucleosis owing to primary Epstein-Barr virus (EBV) infection sometimes causes hepatitis, which is usually self-limiting with mildly elevated transaminases, but can rarely develop into severe hepatitis with jaundice. Objective To clarify the pathogenesis of severe hepatitis by primary EBV infection. Methods We experienced four cases of severe hepatitis with jaundice caused by primary EBV infection. These cases were analyzed virologically and histologically, and compared with infectious mononucleosis patients without jaundice. Results and discussion Using real-time PCR, more EBV-DNA was detected in peripheral blood from patients with severe hepatitis, as compared to those without jaundice. Furthermore, CD3 +, CD4 + or CD8 + cells contained more EBV DNA than did other cell populations, indicating that in severe hepatitis, T cells harbor most of the EBV. By contrast, mainly B cells were infected in infectious mononucleosis patients without jaundice. The liver was biopsied in three of the four cases. An in situ hybridization study showed that EBV infected lymphocytes, not hepatocytes. In addition, in one patient, it was confirmed that the infected lymphocytes were CD8 + T cells. These results suggest that a large EBV burden and T cell infection may play major roles in the mechanism of severe hepatitis caused by primary EB virus infection.

Profuse gastrointestinal haemorrhage due to delayed primary Epstein–Barr virus infection in an immunocompetent adult

Profuse gastrointestinal haemorrhage due to delayed primary Epstein–Barr virus infection in an immunocompetent adult

Fatal Primary Epstein-Barr Virus Infection due to Clonal CD8 + T-Lymphocyte Proliferation in an Immunocompetent Adult

Fatal Primary Epstein-Barr Virus Infection due to Clonal CD8 + T-Lymphocyte Proliferation in an Immunocompetent Adult

The impact of telomere erosion on memory CD8 + T cells in patients with X-linked lymphoproliferative syndrome

Patients with X-linked lymphoproliferative syndrome (XLP) experience excessive T cell proliferation after primary Epstein–Barr virus (EBV) infection, due to mutations in the signalling lymphocyte activation molecule (SLAM) associated protein (SAP) molecule. We examined the impact of dysfunctional proliferative control on the extent of CD8 + T cell differentiation in XLP patients who recovered from primary EBV infection. Although these young patients have normal numbers of lytic and latent EBV-epitope-specific CD8 + T cells, they were extremely differentiated as defined by loss of CCR7 and CD27, low telomerase activity and very short telomeres. This was not a direct effect arising from the loss of SAP, but was due to excessive T cell stimulation due to this defect. Thus, transduction of XLP CD8 + T cells with the catalytic component of telomerase (hTERT), but not SAP, prevented telomere loss and considerably extended proliferative lifespan in vitro . These results indicate that excessive proliferation in CD8 + T cells in XLP patients may lead to end-stage differentiation and loss of functional EBV-specific CD8 + T cells through replicative senescence. This may contribute to the defective immunity found in XLP patients who survive acute EBV infection who develop EBV-related B cell lymphomas before the fourth decade of life.

The immune response to primary EBV infection: a role for natural killer cells

The role of antigen-specific CD3(+)CD8(+) cytotoxic T cells in the control of primary Epstein-Barr Virus (EBV) infection is well established. However, time is required for the antigen-specific immune response to develop and expand. In contrast, innate immune responses, such as natural killer (NK) cells, are considered vital early in the infection process. We analysed the scale, phenotype and function of the NK cell response during symptomatic primary EBV infection, infectious mononucleosis (IM) and showed that NK cell numbers were significantly elevated both at diagnosis of IM and in the first month following diagnosis. There were also significant changes in cell phenotype and function, an increase in the proportion of CD56(bright) cells at diagnosis, and freshly isolated cells showing an enhanced ability to kill EBV-infected cell lines. Moreover, in our cohort of IM patients higher NK cell counts were associated with significantly lower viral load in peripheral blood. Our results suggest NK cells have an important role in the control of primary EBV infection by eliminating infected B cells and augmenting the antigen-specific T cell response via release of immunomodulatory cytokines. The magnitude of the NK cell response may ultimately determine whether primary EBV infection has a clinical outcome.

Drug-induced hypersensitivity syndrome during a primary Epstein-Barr virus infection

Drug-induced hypersensitivity syndrome during a primary Epstein-Barr virus infection

Epstein-Barr Virus

1. Anne K. Junker, MD* 1. *Associate Professor, Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia and Children’s & Women’s Health Centre of British Columbia, Vancouver, BC, Canada Author Disclosure Dr. Junker did not disclose any financial relationships relevant to this article. After completing this article, readers should be able to: 1. Outline the epidemiology of primary Epstein-Barr virus (EBV) infection. 2. Describe and explain the physiologic basis of the clinical features of infectious mononucleosis. 3. Describe and explain the physiologic basis of the common complications of infectious mononucleosis. 4. List the diagnostic tests that can help distinguish acute primary from distant past EBV infection. 5. Review the EBV-associated lymphoproliferative disorders and malignancies. EBV was identified initially in 1964 in tumor tissue from a patient who had African Burkitt lymphoma (BL), a rapidly growing, usually fatal malignancy of the B lymphocyte. When a laboratory technician working with this new virus became ill with mononucleosis and seroconverted to EBV, the link between EBV and mononucleosis became apparent. Soon thereafter, seroepidemiologic studies revealed that EBV infects virtually all of the world’s population, usually as a subclinical or trivial illness in childhood. A decade later, reports of a familial X-linked disorder of fatal infectious mononucleosis highlighted the importance of immunogenetic factors in the management of EBV infection. Now, nearly 40 years after its discovery, EBV continues to captivate clinicians, virologists, oncologists, geneticists, and immunologists attempting to understand this highly successful human pathogen. EBV is a ubiquitous, worldwide pathogen that is harbored persistently by virtually all adults, regardless of geographic location. After primary infection, the virus latently infects circulating B cells and is shed silently into saliva and genital secretions. The colloquial term “kissing disease” acknowledges the oral route by which most people are infected. Spread is associated with close personal contact, so it is not surprising that the age at first infection varies according to living conditions. Infection occurs at an earlier age in the presence of poor hygiene and crowded living conditions; infection rates in …

Serological diagnosis of infectious mononucleosis by chemiluminescent immunoassay using capsid antigen p18 of Epstein-Barr virus

Background Infectious mononucleosis is the common clinical manifestation of primary Epstein-Barr virus (EBV) infection in young children. We evaluated a chemiluminescent immunoassay method for the determination of serum anti-viral capsid antigen IgM antibody and its clinical value in the diagnosis of infectious mononucleosis. Methods Concentrations of the antibody in serum samples from 187 children measured by chemiluminescent immunoassay were compared with those measured by ELISA. Results Assessment of technologic quality (methodology) in diagnostic tests demonstrated that sensitivity of CLIA was 0.64 U/ml and the functional sensitivity was <0.9 U/ml. The within-assay and the between-assay imprecisions of different concentrations were all <5%. Recoveries were all in 93–107%. The linear regression equation between expected values and measured values was y=0.0967+1.0093 x, correlation coefficient was 0.9996 ( p<0.0001). The ROC curve showed that the sensitivity and specificity of the CLIA both were >90%. The area under the curve was 0.992, which was significantly higher than that of ELISA ( p<0.05). Conclusion The CLIA was the excellent method for EBV-VCA IgM measurement at present and can improve the clinical diagnosis of infectious mononucleosis.

Five patients with localized facial eruptions associated with Gianotti-Crosti syndrome caused by primary Epstein-Barr virus infection

Five infants exhibited an exclusively facial rash associated with Gianotti-Crosti syndrome(GCS). On all patient cheeks, multiple erythematous papules were seen symmetrically. All patients tested positive for the immunoglobulin (Ig)M antibody against the Epstein-Barr viral capsid antigen, suggesting that a primary Epstein-Barr virus (EBV) infection caused localized facial rash, an alternative clinical picture of GCS.

Serum epstein–barr virus DNA load in primary epstein–barr virus infection

Specific viral laboratory diagnosis of primary Epstein-Barr Virus (EBV) infection is usually based on antibody-detection assays. During acute, lytic phase of infection, viral DNA can also be detected in serum. In the present study, the diagnostic utility of EBV DNA detection and quantitation in serum in primary EBV infection was investigated. The level of EBV DNA in the serum of 98 immunocompetent patients aged 1-47 years with symptomatic, antibody-confirmed EBV primary infection was assessed using a quantitative real-time PCR assay. The association between viral load and time after onset of disease, age and clinical and laboratory data was investigated. Quantitative PCR detected EBV DNA in 93 of 98 samples (94.9%), and the measured viral loads ranged from 3.8 x 10(1) to 6.6 x 10(4) copies/ml. EBV DNA detection exhibited a sensitivity of 94.9% and a specificity of 97.4% for primary EBV infection. EBV DNA was always detectable until day 12 after onset of symptoms, whereas no further positive PCR results were found after a period of 22 days after onset of disease. Detection of EBV DNA also showed a clearer association with the clinical manifestation of disease than the presence of EBV specific VCA IgG antibodies of low avidity. EBV DNA load was found to correlate inversely with the time after onset of disease (P < 0.001), and higher viral load levels were detected in younger (P = 0.009) and in hospitalized patients (P = 0.038). The results indicate that real-time PCR is a reliable tool for diagnosis of primary EBV infection early in the course of disease. In addition, EBV DNA detection may serve as a useful diagnostic supplement in serologically indeterminate EBV infections.

Genital ulcers caused by Epstein-Barr virus

In North America, the most common cause of vulvar ulcers is infection with herpes simplex virus. However, Epstein-Barr virus can also cause vulvar ulcers, and may be underrecognized. Unlike herpes simplex virus, Epstein-Barr virus is not necessarily sexually transmitted. Therefore, it is particularly important to include in the differential diagnosis of genital ulcers for patients for whom a diagnosis of a venereal infection has important psychosocial consequences. We report three cases of acute primary Epstein-Barr virus infection in which the presenting symptoms were vulvar ulceration.

Viral Infections in Juvenile Myelomonocytic Leukemia: Prevalence and Clinical Implications.

Viral infections may complicate the diagnosis of juvenile myelomonocytic leukemia (JMML) in a substantial proportion of patients, but this possibility has not been tested in a prospective study. The authors therefore measured the cellular expression of the MxA protein, a reliable marker of viral infection, at diagnosis in children with JMML to estimate the prevalence of such infections. Eighteen children, aged 1 to 69 months, who met the diagnostic criteria of the International JMML Working Group were prospectively studied. MxA expression was assessed by flow cytometric analysis of peripheral blood mononuclear cells stained with an antihuman MxA antibody. All data were obtained through the MDS Committee of the Japanese Society of Pediatric Hematology. Twelve patients (67%) had elevated levels of the MxA protein, with rotavirus, RS virus, or CMV infection documented in three of these patients. Although none of the patients had primary Epstein-Barr virus (EBV) infection, reactivation of the virus was strongly suspected in four children, including two with monosomy 7, each having increased levels of MxA. Southern blot analysis revealed monoclonal integration of the EBV genome into bone marrow mononuclear cells from one of these patients. There was no discernible correlation between increases in the marker protein and the presenting features or course of the disease. Viral infection may be present in two thirds of children with newly diagnosed JMML, but it does not constitute a basis for revising clinical management. The possibility that EBV or other viruses contribute to JMML pathogenesis by stimulating pre-exiting malignant clones warrants further investigation.

Syndrome obstructif expiratoire aigu et primo-infection à Epstein-Barr virus

A 3 year-old immunocompetent boy presented with severe obstructive respiratory failure with pneumothorax accompanying a primary Epstein-Barr virus infection. Because of the patient’s severe hypoxemia, he required mechanical ventilation for 6 days. The clinical course with corticosteroids was favourable and the patient was discharged from the intensive care unit without sequelae. Severe pneumonitis with EBV is rare, particularly in children. We describe the clinical course and laboratory test results of this atypical pediatric patient.

The value of prospective monitoring of Epstein-Barr virus DNA in blood samples of pediatric liver transplant recipients.

Post-transplant lymphoproliferative disease (PTLD) is one of the major causes of morbidity and mortality in transplantation patients. A primary Epstein-Barr virus (EBV) infection is a major risk factor for developing PTLD. The aim of this study was to determine circulating EBV DNA after liver transplantation in pediatric patients in relation to primary EBV infection and development of PTLD. EBV serology was performed before transplantation. Every 4 weeks after transplantation a competitive quantitative polymerase chain reaction (PCR) assay for EBV nuclear antigen-1 was performed in 13 patients. Patients were followed for development of a PTLD. Before transplantation four patients were EBV seropositive and nine patients were EBV seronegative. In one of the four patients who were EBV seropositive before transplantation, EBV DNA became detectable after transplantation, with a peak load of 3600 copies/mL. None of these four patients developed a PTLD. Eight of the nine patients who were EBV seronegative before transplantation developed positive EBV DNA samples. EBV DNA was first detected at a mean of 64 days after transplantation (range 38-89). The mean peak EBV DNA load was 79,700 copies/mL (3600-446,000). Two of these patients developed PTLD, but they could not be identified based on prior or concomitant EBV PCR results. In pediatric liver transplantation EBV DNA load is higher in patients with a primary infection than in patients who were EBV seropositive before transplantation. The EBV PCR cannot be used to identify individual patients who develop PTLD. However, elevated EBV DNA load can be used to detect a group of patients at increased risk for PTLD.

Risk of lymphoid neoplasia after cardiothoracic transplantation: the influence of underlying disease and human leukocyte antigen type and matching.

It has been known for more than 20 years that there is an increased risk of lymphoid neoplasia after cardiothoracic transplantation. Recent studies have demonstrated the importance of primary Epstein-Barr virus (EBV) infection and type of immunosuppressive therapy to the cause of these neoplasms, but the contribution of other factors remains equivocal. The authors followed 1,562 patients undergoing cardiothoracic transplantation at Harefield Hospital, United Kingdom, and used standard cohort methods of analysis to examine whether posttransplant lymphoma risk was related to the underlying disease requiring transplantation or the human leukocyte antigen (HLA) type and matching. Lymphomas were categorized into EBV-associated lymphoproliferative disease (LPD) and EBV-negative non-Hodgkin's lymphoma (NHL), and the authors carried out separate analyses of these. The authors found no significant association between the underlying disease necessitating transplantation and the risk of lymphoid neoplasia. There was also no evidence of a relation of lymphoma risk with the presence or absence of any particular HLA antigen, although significant protective effects of HLA-B14 and -B57 were found when analyses were conducted without adjustment for multiple testing. Risk of LPD was not associated with degree of HLA mismatching, but there was a significant effect of mismatching on risk of EBV-negative tumors. The differential effect of HLA mismatching on the risks of LPD and EBV-negative NHL provides further evidence that these two tumors are distinct etiologic entities. The authors' results suggest that the immunologic cause of EBV-negative NHL may be different from that of LPD. Investigation of the relation of risk of EBV-negative NHL to degree of immunosuppression is needed.

Epstein-Barr virus infections of the central nervous system.

Epstein-Barr virus (EBV), a lymphotropic herpes virus causing infectious mononucleosis (IM), also causes various central nervous system (CNS) infections. In the present study, EBV CNS infections were investigated. For adult inpatients in our hospital and related hospitals between 1984-2002, CNS syndromes with IM symptoms were examined, and serologic positives were assessed according to established criteria. Polymerase chain reaction (PCR) was performed for cerebrospinal fluid (CSF) from seven patients. Ten patients with EBV-related CNS infections were found; their mean age was 36 years (20-79 years). The neurologic forms were as follows: acute encephalitis (4 patients), acute cerebellar ataxia (1), acute disseminated encephalomyelitis (ADEM) (2), myelitis (1), and meningitis (2). The PCR from CSF was positive in two patients with meningitis, one patient with ADEM, and one patient with encephalitis-associated chronic EVB infection. One case of encephalitis and another of relapsing ADEM were attributed to chronic EBV infection. Our study identified a variety of EBV-related CNS infections. EBV CNS infections are divided into two groups: 1) CNS syndromes associated with primary EBV or reactivated infection, and 2) those associated with chronic EBV infection; it is notable that in the former, diverse CNS syndromes including ADEM can occur, whereas in the latter, chronic or recurrent CNS syndromes are produced.