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Epstein-Barr virus (EBV) reactivation in COVID-19 patients has been reported, but studies on its clinical significance are lacking. We herein report the occurrence of infectious mononucleosis (IM) due to EBV reactivation in a 60-year-old man with rheumatoid arthritis being treated with methotrexate and tocilizumab. The patient presented with a fever and tested positive for COVID-19. Laboratory findings revealed an increased atypical lymphocyte count, decreased platelet count, and elevated liver enzyme levels. Flow cytometry showed predominant expansion of reactive T cells. EBV reactivation was confirmed using real-time polymerase chain reaction. The patient was treated with remdesivir, and clinical improvement was observed after 10 days of treatment. Follow-up showed a gradual decrease in the EBV-DNA load with no recurrence of atypical lymphocytes. These findings suggest that COVID-19 in immunocompromised patients may lead to unexpected EBV reactivation and IM, even for patients outside the age at which IM is likely to occur. [ABSTRACT FROM AUTHOR]

Diseases of the tonsils and adenoids are extremely common in children and make up a significant part of the paediatric ENT surgeon's practice, as well as presenting frequently to paediatric and primary care teams. The majority of adenotonsillar pathology in children is either infective or obstructive in nature. This article discusses the anatomy and pathophysiology of acute and chronic adenotonsillar disease and discusses how to evaluate a child with suspected adenotonsillar pathology clinically, in both the outpatient and emergency scenario. Surgical management and the adenoidectomy and tonsillectomy techniques are described. The current multidisciplinary working group guidelines regarding surgery for obstructive sleep apnoea in children are also highlighted. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) is a DNA virus that infects 90% of the human population, is responsible for certain cutaneous lymphomas (extranodal NK/T-cell lymhoma, hydroa vacciniforme lymphoproliferative disorder, lymphomatoid granulomatosis, others), and can be associated with a variety of cutaneous manifestations (eg, infectious mononucleosis, severe mosquito bite allergy, chronic active EBV disease, Gianotti-Crosti syndrome). EBV-related skin disorders are frequent in certain populations (South and Cental America, Africa, Asia, and Oceania) and can be diagnostically challenging. The human T-lymphotropic virus type-1 is a retrovirus, which is known to be associated with adult T-cell leukemia/lymphoma, neurologic disorders, but also cutaneous non-neoplastic manifestations (infective dermatitis, infections, and infestations). We performed an updated revision of the clinical dermatologic and histopathologic findings associated with the cutaneous non-neoplastic and preneoplastic disorders occurring in association with the EBV and human T-lymphotropic virus type-1. [ABSTRACT FROM AUTHOR]

It has generally been reported that patients with COVID-19 show a fever, cough, and/or respiratory failure as the most common clinical symptoms but some have unusual symptoms, such as anosmia, diarrhea, and throat pain. We herein report a 26-year-old woman with chief complaints of lymphadenopathy and a fever. First, she underwent a laboratory examination, which showed a high proportion of atypical lymphocytes (19%) and an increase in hepatic enzyme activities, and was then hospitalized with a diagnosis of infectious mononucleosis (IM). However, the blood examination did not show any increase in anti-Epstein-Barr virus VCM-IgM. Subsequently, she developed tonsillar hypertrophy with purulent plugs. An additional examination for infection of other pathogens revealed positivity only for SARS-CoV-2 in a loop-mediated isothermal amplification (LAMP) test. The patient was transferred to the COVID-19-specific isolation ward, and none of the ward staff, patients, or either of the two otolaryngologists who had directly examined this patient showed positive signs for SARS-CoV-2 in a LAMP test. Consequently, this case suggests that even if patients show clinical symptoms and signs of common diseases for otolaryngologists, such as IM, we should keep in mind the possibility of COVID-19 without arbitrarily assuming that IM is caused by Epstein-Barr virus. [ABSTRACT FROM AUTHOR]

Diseases of the tonsils and adenoids are extremely common in children and make up a significant part of the paediatric ENT surgeon's practice, as well as presenting frequently to paediatric and primary care teams. The majority of adenotonsillar pathology in children is either infective or obstructive in nature. This article discusses the anatomy and pathophysiology of acute and chronic adenotonsillar disease and discusses how to evaluate a child with suspected adenotonsillar pathology clinically, in both the outpatient and emergency scenario. Surgical management and the adenoidectomy and tonsillectomy techniques are described. The current multidisciplinary working group guidelines regarding surgery for obstructive sleep apnoea in children are also highlighted. [ABSTRACT FROM AUTHOR]

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. • Recent seroepidemiological evidence suggests that EBV infection initiates prodromal MS disease in susceptible individuals. • Frequency of EBV life cycle stages and their tissue distribution might be altered in MS patients. • Cross-reactive antibody and T cell responses between EBV antigens and myelin autoantigens have been observed in MS patients. • Immune control of autoreactive B and T cell responses might be compromised by EBV infection and improved by HCMV infection. • Alterations of EBV infection and immune control in MS patients could be targeted for disease modification. [ABSTRACT FROM AUTHOR]

Infectious mononucleosis is a common in the pediatric population. Its clinical presentation is rather stereotyped in older children and adolescents, with symptoms made of moderate to high fever, sore throat, fatigue, and lymphadenopathy. Biologically, lymphocytosis, and a mild rise in liver function tests are usual. We report a case of acute acalculous cholecystitis as the initial presentation of infectious mononucleosis in a 12-year-old girl whose main presenting complaints were upper abdominal pain and fever. The diagnosis was confirmed by positive Epstein-Barr virus serology and the typical gallbladder appearance on the abdominal ultrasound. Clinicians are reminded of the existence of this association that, we believe, is likely more frequent than thought earlier. Patients' outcome is spontaneously favorable under supportive therapy alone. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated the diagnostic value of Epstein-Barr virus (EBV) DNA load in blood samples of patients with EBV-associated diseases, and proposed a strategy for the interpretation of positive EBV DNA results.Methods: Derivation and validation cohorts were established to evaluate the clinical significance of EBV DNA loads in the peripheral blood mononuclear cells (PBMCs) and plasma from EBV-infected patients. EBV DNA loads were compared and receiver operating characteristic curves were employed to assess the optimal cutoff values of EBV DNA for identification of EBV-associated diseases.Results: The derivation and validation cohorts comprised 135 and 71 subjects, respectively. EBV DNA loads in the PBMCs of the EBV-associated diseases group was significantly higher than that of the EBV non-associated diseases group (5.8 × 104 vs 7.8 × 103 copies/106 cells, P<0.0001). The diagnostic cut-off value of viral load in PBMCs for EBV-associated diseases was determined to be 1.6 × 104 copies/106 cells. The combined EBV DNA load cutoff in PBMCs and positive EBV DNA qualitative detection in plasma (>500 copies/mL) allowed for the differentiation of EBV-associated and non-associated diseases; the sensitivity and specificity were 80.6 and 96.8%, respectively.Conclusions: The strategy of combining EBV DNA loads in PBMCs and plasma will potentially help identify EBV-associated diseases. [ABSTRACT FROM AUTHOR]

Infectious mononucleosis (IM) develops after primary infection with Epstein-Barr virus. We report a case of septic shock from pelvic inflammatory disease caused by Fusobacterium necrophorum in an adolescent after sexual intercourse during recovery from IM. A 17-year-old girl with a 7-day history of fever was diagnosed with IM. During follow-up, she developed lower abdominal pain and high fever after sexual intercourse and was transferred to our hospital. She was in shock and had a right ovarian abscess. Emergency laparotomy, drainage, and right adnexectomy were performed. F necrophorum was subsequently detected in blood and abscess cultures. [ABSTRACT FROM AUTHOR]

Although infectious mononucleosis due to Epstein-Barr virus (EBV) is a common disease among young individuals, central nervous system (CNS) complications are rare. In this report, we describe a case of CNS complications caused by EBV in a previously healthy young woman. She presented to our hospital with a 9-day history of headache and sore throat, followed by the development of fever and facial edema 6 days prior to admission. On Day 2 of admission, she was confused (Glasgow Coma Scale score: 10 points) and had fever, muscle weakness in her right arm and leg, stiff neck, and roving eye movement. We detected EBV in a cerebrospinal fluid (CSF) sample using a polymerase chain reaction (PCR) test. The magnetic resonance imaging of her brain revealed dural enhancement and right parietal and temporal lobe lesions. She was treated with acyclovir and high-dose steroid therapy. She responded well to treatment, recovered without neurologic sequelae, and was discharged home on Day 12. Our experience suggests that PCR detection of EBV DNA in CSF may be useful in diagnosing EBV encephalitis and that prognosis may be associated with an area of the brain that is affected and the time from symptom onset to starting treatment. [ABSTRACT FROM AUTHOR]

Infectious mononucleosis is a common condition occurring in athletic training rooms. Most cases are due to Epstein-Barr virus infections (upward of 90%). Although treatment generally consists of symptomatic care, there is clinical variation in laboratory workup leading to diagnosis and in the method of return to play decision making. The authors suggest a systematic approach to laboratory evaluation and return to play decisions to minimize clinical variation. The most feared complication of infectious mononucleosis is potential splenic rupture. There have been several examples of the successful use of serial ultrasonography to help make maximally informed return to play decisions. [ABSTRACT FROM AUTHOR]

Objectives: To develop a scale for the severity of mononucleosis.Study Design: One to 5 percent of college students develop infectious mononucleosis annually, and about 10% meet criteria for chronic fatigue syndrome (CFS) 6 months following infectious mononucleosis. We developed a severity of mononucleosis scale based on a review of the literature. College students were enrolled, generally when they were healthy. When the students developed infectious mononucleosis, an assessment was made as to the severity of their infectious mononucleosis independently by 2 physicians using the severity of mononucleosis scale. This scale was correlated with corticosteroid use and hospitalization. Six months following infectious mononucleosis, an assessment is made for recovery from infectious mononucleosis or meeting 1 or more case definitions of CFS.Results: In total, 126 severity of mononucleosis scales were analyzed. The concordance between the 2 physician reviewers was 95%. All 3 hospitalized subjects had severity of mononucleosis scores ≥2. Subjects with severity of mononucleosis scores of ≥1 were 1.83 times as likely to be given corticosteroids. Students with severity of mononucleosis scores of 0 or 1 were less likely to meet more than 1 case definition of CFS 6 months following infectious mononucleosis.Conclusions: The severity of mononucleosis scale has interobserver, concurrent and predictive validity for hospitalization, corticosteroid use, and meeting criteria for CFS 6 months following infectious mononucleosis. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infects about 90% of adults worldwide. It is the main cause of infectious mononucleosis, which is observed most frequently in adolescents. The disease can last several weeks and is characterized by lymphocytosis, sore throat, lymphadenopathy, and fatigue. Exposure to oral secretions during deep kissing has been identified as the major source for primary EBV infection in adolescents. Oral secretions are also thought to be the source for younger children through intimate intact or sharing food and eating utensils, although this has not been confirmed. Unlike most acute viral illnesses such as influenza, the incubation period of symptomatic primary EBV infection is unusually long, lasting about six weeks. Diagnosis is typically made by heterophile antibody tests and/or EBV-specific antibody tests. Long-term consequences may result from acquisition of the virus, including nasopharyngeal carcinoma and lymphomas. Nevertheless, there remains a surprising dearth of knowledge regarding the establishment of an immune response to persistent EBV infection, especially during the incubation period. This lack of knowledge has impaired our ability to develop an effective prophylactic EBV vaccine, despite various attempts. Our greatest challenges in EBV research are to develop a prophylactic vaccine and devise treatment strategies for persons already infected with EBV. [ABSTRACT FROM AUTHOR]

This study compared the performance of 3 automated immunoassays, Architect ® (Abbott), Immulite ® (Siemens) and Liaison ® (Diasorin), for Epstein–Barr virus (EBV) serology. Ninety-one serum samples collected in Amiens University Hospital were analyzed for the presence of Viral Capsid Antigen (VCA) IgG and IgM and Epstein–Barr Nuclear Antigen (EBNA) IgG. The agreement between the 3 assays was calculated for each marker individually and for determination of the EBV profile, based on interpretation of the combination of these 3 EBV markers. Although similar results were obtained with Architect ® and Liaison ® , several discordant results were observed with Immulite ® , particularly for EBNA IgG. A large number of EBNA IgG-positive results were observed, which interfered with interpretation of the EBV profile. In contrast, Immulite ® performed similarly to the 2 other assays for detection of VCA IgM. [ABSTRACT FROM AUTHOR]

Objectives To determine the risk factors for severe infectious mononucleosis (IM) occurrence in immunocompetent adults. Methods We performed a multicenter, retrospective case series including immunocompetent adults presenting with confirmed IM between 2001 and 2011. Severe presentations were compared with uncomplicated presentations using Stata ® 9 software. The significance level was set at 5%. Results In univariate analysis, age over 30 years ( n = 13 or 41.9% vs. n = 5 or 12.8%; P = 0.006), prior use of non-steroidal anti-inflammatory drugs (NSAIDs) ( n = 7 or 87.5% vs. n = 1 or 12.5%; P = 0.009), and smoking ( n = 13 or 68.4% vs. n = 6 or 31.6%; P = 0.013) were associated with severe IM onset. In multivariate analysis, only age over 30 years (OR = 3.55; P = 0.05) and prior use of NSAIDs (OR = 15; P = 0.05) remained associated with severe IM onset, without reaching significance level ( P = 0.05). Conclusion Our study confirmed that age over 30 years is a risk factor for severe IM onset. Prior use of NSAIDs also seems to be correlated with severe presentations. This new data needs to be confirmed in a prospective study. [ABSTRACT FROM AUTHOR]

Background Infectious mononucleosis (IM) and vitamin D deficiency are both risk factors for multiple sclerosis (MS). Objective We wished to establish if IM in the winter months when vitamin D levels are low may be a greater risk factor for MS than IM in the summer months. Methods We identified all patients with MS diagnosed aged 16–60 in a large primary care database in the United Kingdom and matched each by age, sex, general practice and observation period with up to six controls. We identified a coded diagnosis of IM prior to the index date (date of diagnosis). Logistic regression was used to calculate the odds ratio for prior IM exposure in cases versus controls and for winter versus summer exposure in cases and controls with prior IM exposure. Results Based on 9247 cases and 55,033 matched controls (246 and 846 with prior IM respectively), IM was associated with the development of MS (OR 1.77, 95%CI 1.53–2.05) but there was no evidence that IM in the winter as opposed to summer was associated with developing MS (OR 1.09, 95%CI 0.72–1.66). Conclusion We found no evidence that the season of IM influences the risk of subsequent MS. [ABSTRACT FROM AUTHOR]

Monitoring replicative Epstein-Barr virus (EBV) infection still remains a challenge in modern laboratory routine. The immediate-early protein BZLF1 mediates the switch between latent and replicate forms of EBV infection. The aim of this study was to analyze the feasibility of BZLF1 mRNA detection in saliva as a marker for active replication of the virus. Various specimens (saliva, plasma, PBMC) from 17 patients with EBV-induced infectious mononucleosis (IM) and 4 control patients were examined for expression of viral BZLF1 mRNA by means of real-time PCR. BZLF1 expression was correlated to the amount of viral DNA in either compartment. Digestion of plasma and saliva samples with DNase I allowed distinguishing between encapsidated and naked viral DNA. BZLF1 transcripts were found in all different types of specimens in varying frequencies. BZLF1 expression in saliva, PBMC, and plasma correlated with viral load in each compartment. Interestingly, those patients with detectable BZLF1 expression in saliva had a more severe course of infection with longer duration of hospitalization. In conclusion, this study demonstrates the feasibility of BZLF1 mRNA detection in saliva specimens during replicative EBV infection. Its significance for the diagnosis of reactivated EBV infection, particularly under immunosuppression, has to be elucidated in further studies. [ABSTRACT FROM AUTHOR]

Acute pancreatitis and acalculous cholecystitis have been occasionally reported in primary acute symptomatic Epstein-Barr virus infection. We completed a review of the literature and retained 48 scientific reports published between 1966 and 2016 for the final analysis. Acute pancreatitis was recognized in 14 and acalculous cholecystitis in 37 patients with primary acute symptomatic Epstein-Barr virus infection. In all patients, the features of acute pancreatitis or acalculous cholecystitis concurrently developed with those of primary acute symptomatic Epstein-Barr virus infection. Acute pancreatitis and acalculous cholecystitis resolved following a hospital stay of 25 days or less. Acalculous cholecystitis was associated with Gilbert-Meulengracht syndrome in two cases. In conclusion, this thorough analysis indicates that acute pancreatitis and acalculous cholecystitis are unusual but plausible complications of primary acute symptomatic Epstein-Barr virus infection. Pancreatitis and cholecystitis deserve consideration in cases with severe abdominal pain. These complications are usually rather mild and resolve spontaneously without sequelae. [ABSTRACT FROM AUTHOR]

Background The detection of antibodies against Epstein-Barr viral capsid (VCA) and nuclear (EBNA) antigens is routinely performed with different commercially available immunoassays. Objectives In this study, we evaluated the concordance and performance of the Architect ™ chemiluminescent microparticle immunoassays (CMIAs) using Captia ™ enzyme linked immunosorbent assays (ELISA) for VCA IgM, and standard immunofluorescence (IF) assays for VCA IgG and EBNA IgG as comparative techniques. Study design Sera were selected from a heterogeneous population including pediatric and adult patients. Results Concordance between CMIAs and comparative assays was high with total agreement percentages of 84,1% (95% CI: 77.8–88.9) for VCA IgM, 90,6% (95% CI: 84.2–94.7) for EBNA IgG and 98,0% (95% CI: 93.9–99.6) for VCA IgG. Moreover, kappa statistic values showed good to excellent correlation with values of 0.68 (95% CI: 0.57–0.79) for VCA IgM, 0.73 (95% CI: 0.58–0.87) for EBNA IgG and 0.95 (95% CI: 0.89–1.00) for VCA IgG. A correlation was observed between positivity levels on CMIAs and semi-quantitative fluorescence intensity on IF for VCA IgG and EBNA IgG assays. With regard to an accepted gold standard IF assays, CMIA was 98,1% (95% CI: 93.3–99.8) sensitive and 97,4% (95% CI: 86.5–99.9) specific for the detection of VCA IgG. For the detection of EBNA IgG, it was 92,2% (95% CI: 85.1–96.6) sensitive and 84,6% (95% CI: 65.1–95.6) specific. Conclusion In summary, we demonstrated that the CMIA EBV antibody detection panel has high performance and high concordance with other commercially available immunoassays. [ABSTRACT FROM AUTHOR]

Childhood infection with Epstein–Barr virus (EBV) is often asymptomatic and may result in mild flu-like symptoms, but exposure during adolescence and young adulthood can lead to acute infectious mononucleosis (AIM) with a pathology characterized by swollen lymph nodes, sore throat, and severe fatigue lasting weeks or months. A vaccine targeting the envelope glycoprotein gp350 adjuvanted with aluminum hydroxide complexed with the TLR4 agonist monophosphoryl lipid A (MPLA) achieved a 78% reduction in AIM incidence in a small phase II trial of college-age individuals, but development of this vaccine was halted by the manufacturer. Here, we report the evaluation in mice and rabbits of an EBV-gp350 vaccine combined with an adjuvant composed of the synthetic TLR4 agonist glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE). In mice, GLA/SE-adjuvanted gp350 generated high IgG titers (both IgG1 and IgG2a/c subtypes), elevated EBV-neutralizing antibody titers, and robust poly-functional anti-gp350 CD4 + T cell responses. In addition, GLA/SE routinely demonstrated superior performance over aluminum hydroxide in all immunological readouts, including induction of durable neutralizing antibody titers out to at least 1 year post-vaccination. Both components of the GLA/SE adjuvant were found to be required to get optimal responses in both arms of the immune response: specifically, SE for neutralizing antibodies and GLA for induction of T cell responses. Furthermore, this vaccine also elicited high neutralizing antibody titers in a second species, rabbit. These promising results suggest that clinical development of a vaccine comprised of EBV-gp350 plus GLA/SE has the potential to prevent AIM in post-adolescents. [ABSTRACT FROM AUTHOR]

Introduction: Infectious mononucleosis (IM) is a common viral illness that predominantly causes sore throat, fever and cervical lymphadenopathy in adolescents and young adults. Although usually a benign, self-limiting disease, it is associated with a small risk of splenic rupture, which can be life-threatening. It is common practice therefore to advise avoiding vigorous physical activity for at least 4-6 weeks, however this is not based on controlled trials or national guidelines. We reviewed published case reports of splenic rupture occurring in the context of IM in an attempt to ascertain common factors that may predict who is at risk.Method: A search of MEDLINE and EMBASE databases was performed for case reports or series published between 1984 and 2014. In total, 52 articles or abstracts reported 85 cases. Data was extracted and compiled into a Microsoft Excel(®) spreadsheet.Results: The average patient age was 22 years, the majority (70%) being male. The average time between onset of IM symptoms and splenic rupture was 14 days, with a range up to 8 weeks. There was a preceding history of trauma reported in only 14%. Abdominal pain was the commonest presenting complaint of splenic rupture, being present in 88%. 32% were successfully managed non-operatively, whereas 67% underwent splenectomy. Overall mortality was 9%.Conclusions and Recommendations: From our data, it appears that men under 30 within 4 weeks of symptom onset are at highest risk of splenic rupture, therefore particular vigilance in this group is required. As cases have occurred up to 8 weeks after the onset of illness, we would recommend avoidance of sports, heavy lifting and vigorous activity for 8 weeks. Should the patient wish to return to high risk activities prior to this, an USS should be performed to ensure resolution of splenomegaly. The majority of cases reviewed had no preceding trauma, although previous studies have suggested this may be so minor as to go unnoticed by the patient. It is therefore prudent to warn patients about the symptoms of splenic rupture to ensure prompt presentation and minimise treatment delay rather than focusing purely on activity limitation. [ABSTRACT FROM AUTHOR]

• Saliva collection at home is a feasible method to detect EBV DNA and shedding. • Fewer samples from teriflunomide-treated patients with MS were positive for EBV DNA. • Fewer samples from teriflunomide-treated patients with MS were positive for EBV shedding. Given its potential antiviral activity, we investigated the effect of teriflunomide on EBV in patients with relapsing-remitting MS (RRMS). Saliva samples were collected at home and analysed for EBV DNA presence in patients with RRMS treated with teriflunomide for ≥3 months. The proportion of patients with detectable EBV in the teriflunomide cohort was lower than in the reference cohorts. The proportion of samples with EBV DNA or shedding from teriflunomide-treated patients was reduced relative to each reference cohort (P <0.0001; >5.8 virus copies/µL cut-off). This pilot study demonstrated the feasibility of at-home saliva sample collection and revealed a possible effect of teriflunomide on EBV shedding. [Display omitted] [ABSTRACT FROM AUTHOR]

• More rapid antibody responses in college freshmen who contracted a primary EBV infection. • during prospective surveillance correlated with a lower severity of disease. • This effect was most pronounced for p18 IgG. We investigated Epstein-Barr virus (EBV) antibody kinetics in university freshmen who developed laboratory-documented primary EBV infection during prospective studies and correlated these kinetics with disease severity. EBV-naïve participants had blood collected periodically and sera tested for EBV-specific antibodies with line blot and enzyme immunoassays. The line blot assay contained EBNA-1, p18, p23, BZLF-1, p138, and p54 antigens; the enzyme immunoassay contained viral capsid antigen and EBNA-1. Severity of illness (SOI) was graded 0 (asymptomatic) to 6 (bedridden). Participants with maximum SOI scores 0–2 were compared with those whose maximum SOI scores were 3–6. Time to first antibody response was analyzed using the semi-parametric COX model. A total of 201 sera from 38 college students collected before, during, and after primary EBV infection were tested. Earlier antibody responses correlated with milder symptoms. This was most pronounced for late-developing antibodies. The median time to development of p18 IgG was significantly earlier among low-SOI participants (64 days) than high-SOI patients (119 days; P = 0.0003).). Participants with mild disease developed EBNA-1 antibodies sooner than participants with more severe disease (125 days versus >270 days; P = 0.017). Participants with mild disease also showed more rapid loss of antibodies against IgG EA p138 and p54 ≥12 weeks post-infection (P = 0.012 and P = 0.026, respectively). These data suggest that rapid antibody responses to EBV correlate with reduced severity of primary EBV infection. [ABSTRACT FROM AUTHOR]

Vaccine prophylaxis with EBV glycoprotein 350 (gp350) subunit plus adjuvant has been demonstrated clinically to protect individuals against infectious mononucleosis (IM), but the specifications of the antigen required to elicit this protection has remained largely theoretical. Previous studies have shown that antibodies to gp350 comprise the principle component of EBV-neutralizing sera. Further, a murine monoclonal antibody against gp350 (clone 72A1) is able to prevent infection by the virus both in vitro and in vivo . In the present study, we identify the 72A1 epitope on recombinant gp350 antigen as the site required for binding to CD21 on human B cells. We also identify the need for conformational-dependence of the antigen to generate EBV-neutralizing antibodies in vivo . Further, we have characterized the glycosylation status and antigenicity profiles of both native and denatured CHO-produced soluble gp350 as well as non-glycosylated protein produced in Escherichia coli . Collectively our in vitro and in vivo data demonstrate the requirement for a conformationally accessible 72A1 epitope on gp350 to elicit EBV-neutralizing responses, and establish this as a critical attribute of this vaccine antigen. These data provide direction for commercial vaccine development, as the absence of this epitope on either E. coli -expressed or denatured gp350, may limit production and purification options for the antigen. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is a ubiquitous virus that has been implicated in a wide range of human diseases, many of which have mucocutaneous manifestations. As a member of the herpesviridae family, EBV causes lifelong infection by establishing latency in B lymphocytes. An intact immune response is critical in preventing progression of EBV disease, and the clinical manifestations of infection are dependent on the intricate relationship between virus and host immune system. This review provides a comprehensive overview of the epidemiology, pathophysiology, and diagnostic testing in EBV infection. In part I of this continuing medical education article, the mucocutaneous manifestations of EBV infection are reviewed with an emphasis on pathophysiology and management. [ABSTRACT FROM AUTHOR]

Background Previous infection with Epstein–Barr virus (EBV) and a history of infectious mononucleosis (IM) have been previously associated with an increased risk of multiple sclerosis (MS). Whether there are common genetic factors that may partially explain these associations has not been thoroughly explored. Objective To investigate whether select polymorphisms in genes associated with IM susceptibility are related to MS risk—a self-reported history of IM or antibody titer against Epstein–Barr virus nuclear antigen 1 (anti-EBNA1). Methods A case-control study including 1213 MS cases and 454 controls enrolled in the Accelerated Cure Project for MS (ACP) Repository. Select polymorphisms in HLA-A , SH2D1 A and IL15RA and anti-EBNA1 Ab titers were measured using stored blood samples provided by participants. Generalized linear models were used to assess the associations between select polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titers. Results No significant associations were observed between the selected polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titer. Conclusion It is unlikely that any of the studied polymorphisms contribute to the explaining the association between anti-EBNA1 Ab titer or history of IM and MS. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae is a main causative agent of serious invasive bacterial infections. However, concurrent infection with invasive pneumococcal disease (IPD) and viral infectious mononucleosis (IM) is rare. We report an infant with serotype 6C infection causing IPD occurring simultaneously with IM. A previously healthy 11-month-old girl referred to our hospital because of fever, leukopenia, and elevated C-reactive protein presented to us with disturbance of consciousness, tachycardia, tachypnea and agranulocytosis. Other findings included tonsillitis with purulent exudates and white spots, bilateral cervical adenopathy, and hepatosplenomegaly. We diagnosed her illness as sepsis and administered a broad-spectrum antibiotic, an antiviral agent, and granulocyte transfusions. After treatment was initiated, fever gradually decreased and general condition improved. IPD was diagnosed based upon isolation of S. pneumoniae of serotype 6C from blood cultures obtained on admission. Concurrently the girl had IM, based upon quantitation of Epstein-Barr viral DNA copies in blood and fluctuating serum antibody titers. Although simultaneous IPD and IM is a rare occurrence, this possibility is important to keep in mind. [ABSTRACT FROM AUTHOR]

The ubiquitous Epstein- Barr virus ( EBV) is related to the development of several lymphoid and epithelial malignancies and is also the aetiological agent for infectious mononucleosis ( IM). BZLF1, an immediate early gene, plays a key role in modulating the switch from latency to lytic replication, hence enabling viral propagation. Polymorphic variations in the coded protein have been studied in other geographical regions in a search for viral factors that are inherent to malignancies and differ from those present in benign infections. In the present study, in samples of paediatric patients with benign IM and paediatric patients with malignant lymphomas, we detected previously described sequence variations as well as distinctive sequence polymorphisms from our region. By means of phylogenetic reconstruction, we characterized new phylogenetically distinct variants. Moreover, we described an association between specific variants and the studied pathologies in our region, particularly variant BZLF1- A2 with lymphomas and BZLF1- C with IM. Additionally, length polymorphisms within intron 1 were also assessed and compared between pathologies resulting in an association between 29-bp repeated units and lymphomas. In conclusion, this is the first report to characterize BZLF1 gene polymorphisms in paediatric patients from our geographical region and to suggest the association of these polymorphisms with malignant lymphomas. [ABSTRACT FROM AUTHOR]

Purpose Epstein–Barr virus is a common human pathogen which infects the great majority of population worldwide. A striking proliferation of CD8 + T cells is an immune response to EBV invasion of B lymphocytes during infectious mononucleosis. The aim of the study was to analyze frequencies of CD28 + CD95 − , CD28 + CD95 + , CD28 − CD95 + T cell subsets putative naïve ( T N ), central ( T CM ) and effector memory ( T EM ) T cells in children with infectious mononucleosis. Material/methods Multiparameter flow cytometric analysis of CD4 + and CD8 + T cell subsets was performed in 19 children with acute infectious mononucleosis. Results The CD4 + /CD8 + ratio was found to be decreased (0.53) in children with infectious mononucleosis. Median T N , T CM , T EM frequencies were estimated to be 3.7, 4.5, 15.1% of CD8 + and 23, 59.3, 5.5% of CD4 + T cells, respectively. In the present study we demonstrated negative correlations between CD8 + CD28 + CD95 + and CD8 + CD28 − CD95 + T cells and both VCA IgM antibody titers and disease duration. However, no such correlation was found when subset of CD4 + T cells or CD8 + CD28 + CD95 − cells was compared. Conclusions We conclude that there is a rapid decrease in the number of memory CD8 + T cells in early acute stage of infectious mononucleosis. [ABSTRACT FROM AUTHOR]

Epstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50 years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. [ABSTRACT FROM AUTHOR]

Abstract: The Epstein Barr virus (EBV) is associated with several lymphoid and epithelial malignancies such as Hodgkin and Burkitt lymphoma or nasopharyngeal carcinoma and it is also the etiological agent of infectious mononucleosis (IM). Transcriptional regulation of the viral oncoprotein LMP1, remains yet not fully understood. LMP1 expression can be initiated in an EBNA2 dependent or independent manner from ED-L1 or LT-R1 promoters. It has been proposed that sequence variation at ED-L1 region could be an important factor concerning LMP1 expression. In order to characterize the natural sequence variation of the ED-L1 promoter, and its relationship with neoplasia, 44 pediatric patients, 17 IM and 27 EBV-associated lymphoma cases from Argentina, were studied. Phylogenetic analysis showed 4 main clusters, namely B95.8, Raji, Cao and P3HR1. Most isolates, 80.3%, conformed the B95.8 group. Co-infection with more than one viral variant was detected in 5/17 IM cases, but no co-infections were detected among lymphoma cases. Moreover, co-infected IM cases exhibited differences between the ED-L1 sequences obtained from different anatomical compartments. Mutations confined to transcription factor binding sites such as SP1/SP3, CRE, AP2, C/EBP were found in similar proportions in 23 isolates from both benign and malignant samples, rendering the distribution of these mutations not significant among malignant samples. [Copyright &y& Elsevier]

Abstract: Multiple sclerosis (MS) is a disease with multiple etiologies. The most recent theory of the vascular etiology of MS, Chronic Cerebrospinal Venous Insufficiency (CCSVI), suggests that cerebral venous obstruction could lead to cerebral venous reflux, promoting local inflammatory processes. This review article offers strong evidence that the route of the observed narrowing of cerebral veins arises from autonomic nervous system dysfunction, particularly cardiovascular autonomic dysfunction. The dysfunction of this system has two major effects: 1) the reduction of mean arterial blood pressure, which has the potential to reduce the cerebral perfusion pressure and the transmural pressure, and 2) the failure of cerebral autoregulation to maintain constant cerebral blood flow in the face of fluctuations in cerebral perfusion pressure. Alterations in cerebral autoregulation could in turn raise the critical closure pressure, indicated to be the cerebral perfusion pressure at which the transmural pressure will be sub-sufficient to overcome the active tension imparted by the smooth muscle layer of the vessel. These two effects of autonomic nervous system dysfunction (reduction in arterial blood pressure and alterations in cerebral autoregulation), when combined with inflammation-induced high levels of nitric oxide in the brain, will lower transmural pressure sufficiently to the point where the threshold for critical closure pressure is reached, leading to venous closure. In addition, cerebral vessels fail to overcome the closure as a result of low central venous pressure, which is also regulated by autonomic nervous system function. Furthermore, through their neuroregulatory effects, infectious agents such as the Epstein-Barr virus and vitamin D3 are able to alter the functions of the autonomic nervous system, influencing the rate of CCSVI occurrence. The absence of CCSVI specificity for MS, observed in recent clinical studies, may stem from a high prevalence of autonomic nervous system dysfunction in control groups which were recruited to these studies. Future studies should investigate CCSVI in relation to cardiovascular autonomic function. [Copyright &y& Elsevier]

Abstract: Objective: Cervical lymphadenopathy is a common pediatric problem; reactive hyperplasia, specific infective agents, and malignancy are mainly the differential diagnosis. The aim of our study was to detect the prevalence of Epstein–Barr virus infection among children who complained of cervical lymphadenopathy and also to evaluate the clinical manifestations of the disease in pediatric patients. Methods: One hundred and sixty children presented with cervical lymphadenopathy were subjected to Epestien–Barr Virus (EBV) serology testing. Cases that showed positivity to heterophile antibody test, and/or EBV-specific antibodies; IgM against viral capsid antigen (VCA-IgM) and IgG against viral capsid antigen (VCA-IgG) were evaluated clinically for manifestations of the disease. Results: Twenty-four cases (15%) showed positivity to EBV serology, all of them had posterior cervical lymph nodes enlargement, 70.8% had fever, 66.6% had tonsillo-pharyngitis, 58.3% had splenomegaly, 25% had hepatomegaly, 41.6% had generalized lymphadenopathy, while skin rash was detected in 12.5%, and both palatal petechiae and palpebral edema were detected in 8.3%. Conclusions: EBV infection is not a rare cause of cervical lymphadenopathy in children. Posterior cervical lymphadenopathy in pediatric age group may represent a password for suspicion of EBV infection, while other clinical manifestations of the disease may include hepato-splenomegaly, skin rash, palpebral edema and palatal petechiae. [Copyright &y& Elsevier]

Abstract: Objectives: Epstein-Barr Virus (EBV) infection has the potential to establish life-long, benign infections in their hosts. Although biochemical evidence of hepatocellular damage is common, jaundice is uncommon and complete recovery is the rule. The present study describes clinical characteristics and changes of liver function tests during the course of infectious mononucleosis. Patients and methods: All immunocompetent patients with hepatic dysfunction associated with acute EBV infection, cared for at the University Hospital of Heraklion, over a 6-year period, were identified and retrospectively studied. Results: The study included 41 patients with a median age of 18.5 (15–51) years. Aspartate-aminotrasferase (AST) and alanine-aminotrasferase (ALT) were increased in an average maximum of 5-fold. Both transaminase levels started to rise 2days after the clinical onset of the disease, and returned to normal after a period of 20days. Alkaline-phosphatase (ALP), γ-glutamyltransferase (γ-GT) and bilirubin levels also increased above the normal values during the course of the disease and returned to normal after a period of 20, 30 and 22days respectively. The changes of mean AST and ALT levels over time were statistically significant, while those of mean ALP, γ-GT and bilirubin levels over time were not. Anicteric cholestatic liver disease was observed in 24 patients (59%), while icteric only in 2 (6%). Conclusion: Liver involvement in acute EBV infection represents mild and self-limited hepatitis with predominantly cholestatic features. [ABSTRACT FROM AUTHOR]

Abstract: Background: Infectious mononucleosis usually runs a mild self-limiting course. Complications arise rarely and when so, corticosteroids are the mainstay of their treatment. The role of antivirals in the management of severe EBV infections is debatable. Methods: We sought to review the usage of antivirals for severe EBV infection in apparently immunocompetent patients. For this reason a search in PubMed and Scopus was performed for the time period from 1982 to 2009. Results: 45 patients with severe manifestations of infectious mononucleosis received antivirals (as an adjunct to steroids in 26 of them). Specifically 21 patients with CNS involvement (meningoencephalitis, cerebellitis), 4 with peripheral nervous system involvement (Guillain-Barré, myeloradiculitis, facial nerve palsy), 5 with hepatitis and 15 with other afflictions (including adult respiratory distress syndrome, thrombocytopenia, aplastic anemia, acute renal failure, ulcerations, myocarditis, and frosted branch vasculitis) received antiviral medications. Thirty-nine out of these 45 patients had a favourable outcome (27 were cured and 12 showed clinical improvement) while 6 patients died. The most commonly prescribed antiviral regimen was acyclovir monotherapy (35 patients). Three patients received combinations of acyclovir with other antivirals and 1 received famciclovir. Three patients received ganciclovir monotherapy, 1 ganciclovir plus foscarnet, 1 foscarnet and 1 vidarabine. Conclusion: The available data derive from case reports and case series and thus the deduction of conclusions regarding the effect, if any, of antiviral treatment is debatable. However, physicians may consider using antiviral agents in severe manifestations of EBV infections in immunocompetent patients as an adjunct to steroid treatment. [ABSTRACT FROM AUTHOR]

Abstract: Lymph node lesions in infectious mononucleosis (IM) show a marked histologic diversity. We report here three cases of IM lymphadenitis with histologic findings indistinguishable from those of toxoplasmic lymphadenitis. The histologic findings of the three cases presented here showed a histologic triad of toxoplasmic lymphadenitis, including (i) numerous lymphoid follicles with hyperplastic germinal centers; (ii) small clusters or single epithelioid histiocytes; and (iii) multiple foci of monocytoid B-cells. Moreover, all three lesions contained isolated or small clusters of epithelioid histiocytes within the hyperplastic germinal centers and the periphery of lymphoid follicles, which are the most specific histologic findings of toxoplasmic lymphadenitis. However, serologic findings confirmed EBV infection in all three cases. On in situ hybridization, numerous Epstein-Barr virus (EBV)-encoded small RNA (EBER)-positive cells were demonstrated in the germinal center, as well as in interfolicular areas in all three cases. Toxoplasmosis gondii infection was excluded in at least one case, based on serologic findings. Polymerase chain reaction analysis also demonstrated that there was no T. gondii DNA in the remaining two cases. Two of our three cases showed atypical clinical presentations, including an absence of atypical lymphocytosis in peripheral blood in two cases, age more than 30 years, and an absence of systemic symptoms in one case. It appears that previous descriptions emphasize the differential diagnostic problems between IM lymphadenitis and malignant lymphomas. However, from a therapeutic perspective, it is important to discriminate IM lymphadenitis from toxoplasmic lymphadenitis particularly in patients showing atypical clinical features. [Copyright &y& Elsevier]

Background: Miller Fisher syndrome, a variant of Guillain-Barré syndrome, is an acute inflammatory demyelinating polyradiculoneuropathy that may occur weeks after a bacterial or viral infection. Campylobacter jejuni and Haemophilus influenzae are frequently reported etiological agents.Patient Description: We describe a boy with Miller Fisher syndrome following Epstein-002DBarr virus primary infectious mononucleosis. He presented with bilateral dysfunction of several cranial nerves and hyporeflexia of the limbs but without ataxia. Miller Fisher syndrome was confirmed by the presence of anti-GQ1b antibodies in a blood sample. Epstein-Barr virus was identified by polymerase chain reaction and serology.Conclusion: Epstein-Barr virus should be considered as a Miller Fisher syndrome's causative agent. The physiopathology of this condition may involve cross-reactive T-cells against Epstein-Barr virus antigens and gangliosides. [ABSTRACT FROM AUTHOR]

Abstract: Epstein-Barr virus (EBV) infection is a benign disease, which may occasionally be fatal, particularly in children and immunocompromised patients. Epstein-Barr virus infection is rare in elderly subjects and seems to have a self-limited course. A case of fatal liver failure due to chronic active EBV infection in a 75-year-old man is described. The etiology was established postmortem by cellular expression of EBV-DNA in liver and lymphatic tissue. This patient meets the diagnostic criteria of a case definition for a highly probable “severe chronic active EBV syndrome.” Either suspected or unsuspected, the long-term prognosis of this syndrome is poor and its mortality high. [Copyright &y& Elsevier]

Abstract: The association of acute myelopathy and encephalopathy is reported in a 13-year-old boy. Signs and symptoms of infectious mononucleosis, presence of heterophile antibodies, anticapsid antibodies and Epstein-Barr virus DNA detected in cerebrospinal fluid, disclosed a primary or reactivated infection by Epstein-Barr virus. Outcome was rapid and benign with complete clinical recovery in 1 month, after pulse therapy with methylprednisolone. Epstein-Barr virus is a known agent related to acute disseminated encephalomyelitis, by immune mediated mechanisms. However, in this case, cortical involvement in magnetic resonance imaging, short time between infectious mononucleosis and central nervous system manifestations, and the presence of viral DNA in cerebrospinal fluid, raised the possibility of a direct action of the virus in central nervous system. Acute myelopathy associated to Epstein-Barr virus encephalitis has been rarely reported in children. [Copyright &y& Elsevier]

Summary: Objective: The aim of this study was to describe a case of acute acalculous cholecystitis occurring in the course of primary Epstein–Barr virus (EBV) infection. Methods: The clinical features of the case were analyzed and compared to those of three other similar cases reported in the international literature. Results: All cases occurred in European females with cholestatic hepatitis, presented with gallbladder wall thickening, and recovered uneventfully without the need for surgical intervention. Conclusions: Acute acalculous cholecystitis may occur during the course of acute EBV infection, especially in patients with cholestatic hepatitis. Clinicians should be aware of the possible involvement of the gallbladder during EBV infection to avoid unnecessary invasive procedures or the overuse of antibiotics. [Copyright &y& Elsevier]

Abstract: Mitochondrial myopathies are heterogeneous disorders with diverse presentations including laboratory findings of lactic acidosis. Often times they are diagnosed in childhood or the early teenage years following an infectious illness. Minocycline is a common antibiotic used for the treatment of acne. It has been reported to alter mitochondrial respiratory chain complexes. We report an interesting case of a teenager in which mitochondrial myopathy with severe lactic acidosis presented following a bout of infectious mononucleosis and minocycline use. It is hypothesized that oxidative stress from the infectious illness plus the minocycline use triggered the patient''s presentation. The clinical manifestations and genetics of mitochondrial myopathies and treatment are discussed along with the management of lactic acidosis. [Copyright &y& Elsevier]

Summary: A 37-year-old man was presented with incidental findings of neutropenia, atypical lymphocytosis, thrombocytopenia and deranged liver parenchymal enzymes. Four days later, he developed fever, sore throat and cervical lymphadenopathy, compatible with mononucleosis-like illness (MLI). Polymerase chain reaction (PCR) and viral culture of the nasopharyngeal swab showed human metapneumovirus (hMPV). There was a ≥4-fold rise in IgG against hMPV. This is the first case report illustrating the natural clinical course of hMPV-related MLI. [Copyright &y& Elsevier]

Abstract: The mechanisms leading to CNS disorders after EBV infections are unclear. We report the case of a patient who developed a severe, but reversible, encephalopathy following an infectious mononucleosis. We detected no EBV DNA in the blood or in the cerebrospinal fluid (CSF) and no EBV-specific antibodies in the CSF. However, we found a potent MOG-specific cellular and humoral immune response. Interestingly, MOG-specific cellular immune response rapidly decreased, paralleling the improvement of clinical condition. In conclusion, this detailed study shows that acute EBV infection can trigger a potent auto-inflammatory response in the CNS, without evidence of an overt infection. [Copyright &y& Elsevier]

Summary: We describe an adolescent boy who presented with acute sinusitis complicating Epstein-Barr virus-induced infectious mononucleosis. Supportive and antibiotic treatment led to a full recovery. [Copyright &y& Elsevier]

Abstract: Background: Infectious mononucleosis decreases the productivity of many college students and Epstein–Barr virus (EBV) infection may result in long-term immune damage. Objectives: Evaluate the antiviral effect of valacyclovir during EBV-related acute infectious mononucleosis and explore potential clinical benefits. Study design: University students who presented during the first 7 days of illness were randomized to receive valacyclovir 3g/day for 14 days or not. The quantity of Epstein–Barr virus (EBV) DNA in oral and whole blood samples was determined by real-time (TaqMan) PCR. The primary outcome was the proportion of subjects with laboratory-confirmed primary EBV infection who had ≥2log10 decrease in EBV copies/mL in oral washes during the treatment period. Secondary outcomes included clinical effects. Results: Twenty subjects were studied. The proportion of valacyclovir recipients versus control subjects who had ≥2log10 decrease in EBV copies was significantly greater for both oral wash fluid-derived cell pellet (P =0.03) and supernatant (P =0.001) samples. At the end of the treatment period, the number of reported symptoms (P =0.03) and the severity of illness (P =0.049) were reduced among valacyclovir recipients as compared with controls. Conclusions: Valacyclovir therapy caused a reduction of EBV excretion and possibly produced a clinical benefit in infectious mononucleosis. Because our study was small and not placebo-controlled, these results must be confirmed by a larger, placebo-controlled trial. [Copyright &y& Elsevier]

Abstract: Infectious mononucleosis, caused by primary Epstein-Barr virus (EBV) infection, is usually a benign, self-limited lymphoproliferative disorder. We report a case of a 21-year-old woman who presented with fever, sore throat, severe neutropenia, and absolute lymphocytosis with atypical lymphocytes. In situ hybridization for EBV-encoded small RNA performed on the marrow aspirate clot specimen demonstrated scattered positive cells. EBV serology was compatible with primary infection. Flow cytometry immunophenotypic studies performed on aspirate material revealed a profoundly expanded population of CD8+ T-cell receptor (TCR)-αβ T cells with uniform expression of CD94. No evidence of a monoclonal T-cell population was found as assessed by V β use with flow cytometry and by TCR γ-chain gene rearrangement using a polymerase chain reaction method. Uniform expression of CD94 in an exuberant reactive proliferation of CD8+ TCR-αβ T cells in infectious mononucleosis has not been reported previously, and combined with atypical morphology might be misinterpreted as a malignant neoplasm. [Copyright &y& Elsevier]