Primary Epstein-Barr Virus Infection Research Articles

Altered EBV specific immune control in multiple sclerosis

Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have shown that this alteration after primary EBV infection identifies individuals with a more than 30-fold increased risk to develop MS. The mechanisms by which EBV infection might erode tolerance for the central nervous system (CNS) in these individuals, years prior to clinical MS onset, remain unclear. In this review I will discuss altered frequencies of EBV life cycle stages and their tissue distribution, EBV with CNS autoantigen cross-reactive immune responses and loss of immune control for autoreactive B and T cells as possible mechanisms. This discussion is intended to stimulate future studies into these mechanisms with the aim to identify candidates for interventions that might correct EBV specific immune control and/or resulting cross-reactivities with CNS autoantigens in MS patients and thereby ameliorate disease activity.

Primary Active Epstein-Barr Virus Infection Coexisting with Immune Thrombocytopenia in Children-A Rare Trigger Factor of Immun Thrombocytopenia: Two Case Reports

Immune thrombocytopenia (ITP) is a reason of thrombocytopenia that is characterized by isolated thrombocytopenia in childhood. Epstein barr virus infection (EBV) is a mildly and uncomplicated ailment that might be a trigger factor for ITP. Here, we discuss two cases with ITP secondary Epstein barr virus infection.

Risk of multiple sclerosis in individuals with infectious mononucleosis: a national population-based cohort study using hospital records in England, 2003-2023.

Epstein-Barr virus (EBV) is thought to be a necessary causative agent in the development of multiple sclerosis (MS). Infectious mononucleosis (IM), which occurs up to 70% of adolescents and young adults with primary EBV infection, appears to be a further risk factor but few studies have been highly powered enough to explore this association by time since IM diagnosis. The objective was to quantify the risk of MS in individuals with IM compared with the general population, with particular focus on time since IM diagnosis. In this retrospective cohort study using English national Hospital Episode Statistics from 2003 to 2023, patients with a hospital diagnosis of IM were compared with the general population for MS incidence. MS incidence in patients with IM was nearly three times higher than the general population after multivariable adjustment (adjusted hazard ratio = 2.8, 95% confidence interval (CI = 2.3-3.4), driven by strong associations at long time intervals (>5 years) between IM diagnosis and subsequent MS diagnosis. While EBV infection may be a prerequisite for MS, the disease process of IM (i.e. the body's defective immune response to primary EBV infection) seems to be, in addition, implicated over the long term.

Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infectedtransformed B cells.

Epstein - Barr Virus Salivary Shedding in Patients with Acute Infectious Diseases: A Pilot Study.

Epstein-Barr virus (EBV) is a widely disseminated herpesvirus for which antibodies have been demonstrated in over 90% of adults worldwide. After subclinical primary EBV infections, as well as after infectious mononucleosis, the virus can be shed in saliva for a prolonged period of time. Diseases and disorders that can induce EBV salivary shedding include mental disorders and sex, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, malaria and HIV infection. Since the occurrence of EBV in saliva during acute infectious diseases has not yet been systematically researched, we aimed to investigate the possible relationship between acute infectious diseases and salivary shedding of EBV. This pilot cross-sectional study included consenting adults hospitalized for acute infectious conditions and their peers free of acute infectious diseases. A total of 40 patients with acute infectious diseases were enrolled, along with 41 adults free of acute infections. Peripheral venous blood samples for serodiagnosis and saliva samples for EBV PCR testing were collected from both groups. We fitted logit and general linear models to proportions and to ln (viral copy counts) to generate adjusted proportions and geometric mean values in the two groups of subjects. We used SAS for Windows 9.4. The most common acute infectious disease was COVID-19 pneumonia, followed by hemorrhagic fever with renal syndrome. Crude proportions of people with positive serological test results and those with saliva viral shedding were similar in the two groups. The presented preliminary data do not indicate acute infectious conditions as a marked "contributor" in increasing salivary EBV shedding.

Epidemiology of Epstein-Barr Virus Chronic High Viral Load in Kidney Transplant Recipients

Background. Epstein-Barr virus (EBV) chronic high viral load (CHVL) may be defined by >16 000 copies/mL whole blood or >200 copies/105 peripheral blood mononuclear cells in >50% samples exceeding 6 mo. EBV CHVL has only been characterized in a few small pediatric studies, with heterogeneous results and unclear clinical significance. Methods. This single-center observational study evaluated adult and pediatric kidney transplant recipients transplanted between 2010 and 2021 on tacrolimus/mycophenolate-based/prednisone immunosuppression. The primary outcome was EBV CHVL prevalence. Secondary outcomes included recipient characteristics, DNAemia kinetics, and posttransplant lymphoproliferative disorder (PTLD) in recipients with EBV CHVL versus low-grade DNAemia or no DNAemia. Results. Five hundred forty-one recipients had a mean follow-up of 4.6 y. Fourteen recipients (2.6%) developed EBV CHVL, 70 (12.9%) had low-grade EBV DNAemia, and 457 (84.5%) had no EBV DNAemia. EBV CHVL was more common in recipients who were Caucasian (P = 0.04), younger (P = 0.04), received induction immunosuppression (P = 0.02), and had high-risk donor–recipient EBV serologic mismatch (P < 0.0001). CHVL patients had a higher first viral load (P = 0.03), longer time to maximum viral load (P = 0.02), and did not achieve sustained DNAemia clearance versus low-grade DNAemia. Three EBV-positive PTLD cases occurred in recipients with a history of EBV DNAemia. PTLD was present in 7.1% (1/14) CHVL versus 2.9% (2/70) low-grade DNAemia patients (P = 0.002). EBV DNAemia developed in 32 EBV seronegative recipients (32/59; 54%); clearance was achieved in 70% (14/20) with low-grade DNAemia but no CHVL (0/12; P = 0.0001). Conclusions. CHVL was uncommon and appeared to occur after primary EBV infection. Future studies should explore other potentially modifiable risk factors for PTLD, including optimal management of EBV DNAemia.

Comparison of plasma proteomic profiles of patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and infectious mononucleosis.

Primary Epstein-Barr virus (EBV) infection occasionally causes EBV-infectious mononucleosis (EBV-IM) and EBV-hemophagocytic lymphohistiocytosis (EBV-HLH). Although EBV-IM is mostly mild and self-limiting, EBV-HLH is a life-threatening disease characterized by excessive immune activation. However, the pathogenesis of EBV-HLH is yet to be fully elucidated. A diagnostic biomarker for EBV-HLH is desirable because early diagnosis and treatment are critical for the effective management of patients. In this study, the proteomic profiling of plasma was performed using liquid chromatography-mass spectrometry to identify proteins specific to EBV-IM and EBV-HLH. Furthermore, pathway analysis was performed for the proteins upregulated in patients with EBV-IM and EBV-HLH. Compared to healthy controls, 63 and 18 proteins were upregulated in patients with EBV-IM and EBV-HLH, respectively. Pathway and process enrichment analyses revealed that the complement system was the most enriched category of upregulated proteins in EBV-IM, whereas proteins related to immune effector processes were the most enriched in EBV-HLH. Among the 18 proteins upregulated in EBV-HLH, seven were exclusive to EBV-HLH. These specific proteins were associated with three pathways, and apolipoprotein E was commonly found in all the pathways. Proteomic analysis may provide new insights into the host response to EBV infection and the pathogenesis of EBV-related diseases.

Tonsillar cytotoxic CD4 T cells are involved in the control of EBV primary infection in children

CD4 T cells play a key role in Epstein Barr virus (EBV) infection, by modulating latent antigen expression, and exhibiting cytotoxic and regulatory properties. Our aim was to evaluate the presence of Granzyme B (GZMB) and Foxp3 CD4 T cells at different EBV infection status and latency profiles. We examined CD4, GZMB, Foxp3, IL10, TGF-β, CD4-GZMB and CD4-Foxp3 expression at the tonsils of pediatric patients with different infective status and EBV latency profiles. CD4+, GZMB+, Foxp3+, CD4-GZMB+ and CD4-Foxp3+ cell counts were higher at the interfollicular region. Higher expression of CD4-GZMB was found in primary infected patients compared to healthy carriers. In patients that expressed latency III antigens, we demonstrated lower CD4+, CD4-GZMB+, CD4-Foxp3+ expression; a negative correlation between the immunoregulatory cytokine IL-10+ and GZMB+ as well as a positive correlation of IL-10+ and CD4+. In patients expressing the lytic protein BMRF1, a positive correlation of TGF-β+ with CD4-GZMB+ and CD4-Foxp3+ was observed. Our findings indicate that CD4-GZMB+ cells are involved in the restriction of primary EBV infection in pediatric patients, which could partially explain the lack of symptoms, whereas both CD4-GZMB+ and CD4-Foxp3+ cells could be involved in the modulation of latency.

Paralisi periferica bilateale del VII nervo cranico da infezione da virus di Epstein-Barr

Following a primary Epstein-Barr virus infection, a 4- years-old boy develops bilateral peripheral VII cranial nerve palsy. Ruled out the other bilateral facial palsy’s causes (first of all borreliosis), the cause of the paralysis is recognized in the Epstein-Barr virus infection. We start a steroid therapy associated with physiotherapy treatment for functional rehabilitation. Bilateral peripheral facial palsy is a rare condition. Un- like unilateral palsy, which is idiopathic in about half of the cases, bilateral palsy is idiopathic in only 20% of cas- es. Both in the case of unilateral and bilateral involve- ment, Borrelia burgdorferi infection stands out among the recognized causes in first place. Another bilateral facial palsy’s cause is Epstein-Barr virus infection, because of its important neurotropism, which causes palsy with a still unclear mechanism. About 2 months after the onset of neurological symptoms our boy is gradually recovering facial nerve functions.

Safety Summary of Pediatric Inflammatory Bowel Disease Therapies

Therapeutic options for the treatment of pediatric inflammatory bowel disease include aminosalicylates, enteral nutrition , corticosteroids, immunomodulators , biologics, and emerging small molecule agents. Infectious risk due to systemic immunosuppression should be mitigated by appropriate screening before therapy initiation. Rare but serious malignancies have been associated with thiopurine use alone and in combination with anti-tumor necrosis factor agents, often in the setting of a primary Epstein–Barr virus infection. Potential agent-specific adverse events such as cytopenias , hepatotoxicity , and nephrotoxicity warrant regular clinical and laboratory monitoring.

Changes in the gut microbiome can predict and decrease Epstein-Barr virus infection risk in children after liver transplantation.

Primary Epstein-Barr virus (EBV) infection is observed in 60% of children during the first year after liver transplantation as usage of imm-unosuppressant. Finding predictive indicators of EBV infection is important to reduce the morbidity and mortality of EBV infection-related diseases by suggesting a dose reduction of immunosuppressant. We compared and analysed the gut microbiome of EBV-infected children with an asymptomatic virus-carrying status and EBV-uninfected children after liver transplantation using high-throughput sequencing. Significant differences in gut microbiome composition in two groups were detected. In detail, Firmicutes and Lactobacillus were increased in EBV-infected group, while Clostridium was increased in EBV-uninfected group. Furthermore, CD4 percentage in T cells of blood showed a significant positive correlation with the content of Clostridium sp. CAG: 127 in EBV-uninfected group. Changes in the gut microbiome could predict and decrease the EBV infection risk of children after liver transplantation.

T cell-mediated immunity during Epstein-Barr virus infections in children.

Epstein-Barr virus (EBV) infection is extremely common worldwide, with approximately 90% of adults testing positive for EBV antibodies. Human are susceptible to EBV infection, and primary EBV infection typically occurs early in life. EBV infection can cause infectious mononucleosis (IM) as well as some severe non-neoplastic diseases, such as chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which can have a heavy disease burden. After primary EBV infection, individuals develop robust EBV-specific T cell immune responses, with EBV-specific CD8+ and part of CD4+ T cells functioning as cytotoxic T cells, defending against virus. Different proteins expressed during EBV's lytic replication and latent proliferation can cause varying degrees of cellular immune responses. Strong T cell immunity plays a key role in controlling infection by decreasing viral load and eliminating infected cells. However, the virus persists as latent infection in EBV healthy carriers even with robust T cell immune response. When reactivated, it undergoes lytic replication and then transmits virions to a new host. Currently, the relationship between the pathogenesis of lymphoproliferative diseases and the adaptive immune system is still not fully clarified and needs to be explored in the future. Investigating the T cell immune responses evoked by EBV and utilizing this knowledge to design promising prophylactic vaccines are urgent issues for future research due to the importance of T cell immunity.

A case of Epstein–Barr virus infection presenting with facial nerve palsy following the precursor condition of hemophagocytic lymphohistiocytosis

AbstractA 25‐year‐old man with infectious mononucleosis caused by Epstein–Barr virus infection developed facial nerve palsy. He was admitted to the hospital due to prolonged fever with liver enzyme elevations, diagnosed as primary Epstein–Barr virus infection. During conservative management, his fever and liver dysfunction persisted, with elevated serum inflammatory marker levels, and the precursor state of Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis was suspected. Although his symptoms and liver dysfunction trended toward amelioration after short‐term prednisolone, left‐sided facial palsy developed acutely. Facial palsy was considered Epstein–Barr virus infection‐related, and he recovered within 1 month following additional steroid therapy. Given the presence of the precursor condition of hemophagocytic lymphohistiocytosis just prior to facial palsy, hypercytokinemia was considered a possible pathogenic mechanism for the facial palsy. In patients with Epstein–Barr virus infection, facial palsy may occur independently of the recovery of other symptoms, and cytokine disturbance may affect its development.

Treatment Options for Epstein-Barr Virus-Related Disorders of the Central Nervous System.

Epstein-Barr virus (EBV), a causative agent for several types of lymphomas and mucosal cancers, is a human lymphotropic herpesvirus with the capacity to establish lifelong latent infection. More than 90% of the human population worldwide is infected. The primary infection is usually asymptomatic in childhood, whereas infectious mononucleosis (IM) is common when the infection occurs in adolescence. Primary EBV infection, with or without IM, or reactivation of latent infection in immunocompromised individuals have been associated with a wide range of neurologic conditions, such as encephalitis, meningitis, acute disseminated encephalomyelitis, and cerebellitis. EBV is also involved in malignant lymphomas in the brain. An increasing number of reports on EBV-related disorders of the central nervous system (CNS) including the convincing association with multiple sclerosis (MS) have put in focus EBV-related conditions beyond its established link to malignancies. In this review, we present the clinical manifestations of EBV-related CNS-disorders, put them in the context of known EBV biology and focus on available treatment options and future therapeutic approaches.

Cholestatic Jaundice during Epstein-Barr Virus Primary Infection: A Rare Manifestation

Infectious mononucleosis, induced by the Epstein-Barr virus (EBV), is a very frequent infection, affecting mostly young adults. Although liver damage is often mild and self-limiting, only a few cases of severe EBV-induced cholestatic hepatitis and jaundice have been reported in the literature. EBV infection should be considered as part of the differential diagnosis in patients with an obstructive pattern on liver function tests without evidence of biliary obstruction demonstrated on advanced imaging. The diagnosis is usually confirmed only by serology and the evolution is generally favorable. We report the observation of an 16 year old female with no particular medical history, who developed a febrile cholestatic jaundice without signs of hemolysis and without biliary obsruction on imagery.

Epstein Barr Virus Hepatitis-A Mild Clinical Symptom or a Threat?

The present study aimed to characterize pediatric patients diagnosed with hepatitis associated with primary Epstein-Barr Virus (EBV) infection. We described the changes in liver aminotransferases activity during the disease, and we analyzed the results of abdominal ultrasonography. A retrospective study was performed by analyzing the medical records of 166 immunocompetent children diagnosed with primary EBV hepatitis hospitalized at the Department of Children's Infectious Diseases, Medical University of Warsaw, Regional Hospital of Infectious Diseases in Warsaw, between August 2017 and March 2023. Elevated alanine aminotransferase (ALT) activity was noted in the first three weeks of the disease. In 46.3% of patients, ALT values exceeded five times the upper limit of the laboratory norm in the first week of illness. Aspartate aminotransferase activity increased from the first to fourth week from the onset of symptoms and showed two peaks in the first and third weeks. The changes over time of mean AST activity demonstrated significance. Transient cholestatic liver disease was the predominant type of hepatic involvement in 10.8% of children; 66.6% of them were older than 15 years. Clinical and ultrasound criteria of acute acalculous cholecystitis (AAC) were met in three female patients over 16 years of age. Hepatitis associated with primary EBV infection is usually a mild and self-limiting condition. Significantly elevated values of liver enzymes with features of cholestatic liver disease may occur in patients with a more severe course of the infection.

Infectious Mononucleosis: A Case Report with Unusual Features and EBV Induced Hepatitis

Despite the fact that Epstein-Barr virus (EBV) infections are common, we continue to hear about new cases of the illness with bizarre and unique symptoms, which prompts the issue of how well we understand this disease. In developing countries, the average age at which an infection is contracted is rising. Other physical symptoms are less noticeable and liver involvement is more noticeable throughout these stages. To inform healthcare professionals of this change, an update on infectious mononucleosis (IM) variable manifestation is necessary. Although our patient didn't have many physical symptoms, blood testing revealed a typical picture of EBV-induced hepatitis. This instance is consistent with recent research suggesting that hepatic involvement is among the most noticeable symptoms in adults with primary EBV infection. Keywords: [Epstein-Barr virus, Infectious mononucleosis, Hepatitis]

Identification of ADA as a Biomarker for Atypical Epstein Barr Virus Infection in Children.

This study aims to explore the ability of adenosine deaminase (ADA) to discriminate atypical Epstein Barr virus (EBV) infection in children from acute febrile illness. All children admitted to the Children's Hospital of Soochow University between 2018 and 2019, who were acute febrile patients and subjected to the plasma EBV-DNA polymerase chain reaction (PCR) and indirect immunofluorescence (IIF) assay for EBV-specific antibodies assays. The diagnostic value of each detection index was compared by the area under the ROC curve. In children with atypical Epstein Barr virus infection, the sensitivity, specificity, positive predictive value, negative predictive value and Youden index were 62.87%, 100.00%,100.00%, 61.73% and 0.63 for EBV-DNA PCR assay, 80.84%, 100.00%, 100.00%, 75.76% and 0.81 for VCA-IgG avidity and 89.22%, 87.00%, 91.98%, 82.86% and 0.76 for ADA. VCA-IgG avidity (AUC=0.904, P<0.01) and ADA (AUC=0.881, P<0.01) assays had the great diagnostic efficiency. In addition, the sensitivity, specificity and AUC were 92.75%,91.43% and 0.921(95%CI: 0.856-0.985) for ADA in the course≤3 days group, respectively. ADA has a good diagnostic value in the early stage of atypical EBV infection, and is not affected by primary EBV infection and reactivation. SCHLüSSELWöRTER: Adenosine deaminase, Epstein -Barr virus, Biomarker, children.

Comparative Analysis of Primary and Reactivated EB Virus Infection Associated Hemophagocytic Lymphohistiocytosis

To compare the clinical characteristics of children with hemophagocytic lymphocytosis (HLH) associated with primary Epstein-Barr virus (EBV) infection and EBV reactivation, and explore the effects of different EBV infection status on the clinical indexes and prognosis of HLH. The clinical data of 51 children with EBV associated HLH treated in Henan Children's Hospital from June 2016 to June 2021 were collected. According to the detection results of plasma EBV antibody spectrum, they were divided into EBV primary infection-associated HLH group (18 cases) and EBV reactivation-associated HLH group (33 cases). The clinical features, laboratory indexes and prognosis of the two groups were analyzed and compared. There were no significant differences in age, gender, hepatomegaly, splenomegaly, lymphadenopathy, neutrophil count in peripheral blood, hemoglobin content, platelet count, plasma EBV-DNA load, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, albumin, fibrinogen, triglyceride, ferritin, hemophagocytosis in bone marrow, NK cell activity and sCD25 between the two groups(P>0.05). The central nervous system involvement and CD4/CD8 in EBV reactivation-associated HLH group were significantly higher than those in primary infection-associated HLH group, but the total bilirubin was significantly lower than that in primary infection-associated HLH group (P<0.05). After treatment according to HLH-2004 protocol, the remission rate, 5-year OS rate and 5-year EFS rate of patients in EBV reactivation-associated HLH group were significantly lower than those in EBV primary infection-associated HLH group (P<0.05). EBV reactivation-associated HLH is more likely to cause central nervous system involvement and the prognosis is worser than EBV primary infection-associated HLH, which requires intensive treatment.

Characteristics of plasma Epstein-Barr virus DNA in children with primary infection

Objective: To explore the characteristics of plasma Epstein-Barr virus (EBV) DNA in primary infection in pediatric cases. Methods: The laboratory and clinical data of 571 children diagnosed with EBV primary infection in Children's Hospital of Fudan University during September 1st, 2017 to September 30th, 2018 were retrospectively analyzed. According to the results of plasma EBV DNA, they were divided into positive group and negative group. According to the EBV DNA, they were devided into high plasma virol load group and low plasma virol load group. The Chi-square test, Wilcoxon rank sum test were used to compare the differences between groups. Results: Among the 571 children with EBV primary infection, 334 were males and 237 were females. The age of first diagnosis was 3.8 (2.2, 5.7) years. There were 255 cases in positive group and 316 cases in negative group. The percentage of cases with fever,hepatomegaly and (or) splenomegaly, elevated transaminase in the positive group were higher than those in the negative group (235 cases (92.2%) vs. 255 cases (80.7%), χ2=15.22, P<0.001; 169 cases (66.3%) vs. 85 cases (26.9%), χ2=96.80, P<0.001; and 144 cases (56.5%) vs. 120 cases (38.0%), χ2=18.27, P<0.001; respectively).In the positive group, 70 cases were followed up for 46 (27, 106) days, 68 cases (97.1%) turned negative within 28 days, with the exception of 2 cases (2.9%) developed chronic active EBV infection by follow-up revision.There were 218 cases in high plasma viral DNA copies group and 37 cases in low copies group. More cases presented with elevated transaminases in the high plasma viral DNA copies group than those in the low group (75.7% (28/37) vs. 56.0%(116/207), χ2=5.00, P=0.025).Both the positive rate of EBV DNA in peripheral blood leukocytes (84.2% (266/316) vs. 44.7% (255/571), χ2=76.26, P<0.001) and the copies of EBV DNA (7.0×107 (1.3×107, 3.0×108) vs. 3.1×106 (1.6×106, 6.1×106) copies /L, Z=15.23, P<0.001) were higher than that of plasma. Conclusions: In immunocompetent pediatric cases diagnosed as EBV primary infection, cases with positive plasma EBV DNA were prone to have fever, hepatomegaly and (or) splenomegaly, and elevated transaminase than those with negative plasma viral DNA. The plasma EBV DNA usually turns negative within 28 days after initial diagnosis.Most cases with high viral load in plasma showed elevated aminotransferase.