Raman spectroscopy of lymphocytes from patients with the Epstein-Barr virus infection.

In this study, Raman spectroscopy is applied to trace lymphocytes activation following contact with the Epstein-Barr virus (EBV) of the herpesvirus family. The biomarker of cell activation is found to be the 520 cm-1 band, indicating formation of immunoglobulins. The blood samples are obtained from patients diagnosed with infectious mononucleosis and treated at the University Hospital in Kraków. The lymphocytes' Raman spectra are collected using a mapping technique, exciting samples with a 514.5 nm line of Ar + laser. Measurements are performed on the 1st, 4th, 6th, 12th and 30th day of hospitalization, until the patient has recovered. The highest intensity of the immunoglobulin marker is observed on the 4th day of hospitalization, while the results of the blood count of patients show the greatest increase in the number of lymphocytes at the beginning of hospitalization. No activated lymphocytes were observed in the blood of healthy volunteers. Some information is provided by the evaluation of B-cell activation by estimating the activated areas in the cells, which are determined by the presence of the Ig marker. The 900 cm-1 band and band around 1450 cm-1 are also analyzed as markers of the presence of the latent membrane protein, LMP2A (and 2B), of the EBV viral protein. The anomalous degree of depolarization observed in B-cells in the course of EBV infection appears to be due to the influence of a virus protein, disrupting BCR signal transduction.

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 infected transformed B cells.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Infectious mononucleosis: new concepts in clinical presentation, epidemiology, and host response.

PURPOSE OF REVIEW: Infectious mononucleosis (IM) is an infectious disease that presents clinically in only a small percentage of individuals despite almost universal infection with the causative agent. Here, we review the latest concepts in the clinical presentation, epidemiology, and host response of this disease. RECENT FINDINGS: Several recently published papers/reviews describe IM as a condition caused by one of several etiologic agents including, cytomegalovirus (HHV-5), Roseola virus (HHV-6) and Toxoplasmosis amongst others; this review focuses on IM as solely caused by the human herpes virus 4 (HHV-4). Since the initial discovery of the virus in the 1960s and its subsequent discovery as the primary etiologic agent for IM it has been associated with several human cancers and autoimmune disorders. Recent published findings show a correlation between HHV-4 and the autoimmune disorder, multiple sclerosis (MS), suggesting earlier IM could possibly act as a causative factor. Considering the important links being made with IM to so many cancers and autoimmune disorders it is surprising that a standard investigative procedure has yet to be determined for this disease. A standard approach to the investigation of IM would ensure more cases are diagnosed, particularly atypical cases, this would benefit epidemiological studies, and more immediately help practitioners distinguish viral from bacterial throat infections, enabling them to treat accordingly. SUMMARY: The understanding of the latest concepts in clinical presentation, epidemiology and host response to IM would benefit greatly from the introduction of a standard procedure for its investigation and diagnosis.

Epstein-Barr virus: the mastermind of immune chaos.

The Epstein-Barr virus (EBV) is a ubiquitous human pathogen linked to various diseases, including infectious mononucleosis and multiple types of cancer. To control and eliminate EBV, the host's immune system deploys its most potent defenses, including pattern recognition receptors, Natural Killer cells, CD8+ and CD4+ T cells, among others. The interaction between EBV and the human immune system is complex and multifaceted. EBV employs a variety of strategies to evade detection and elimination by both the innate and adaptive immune systems. This demonstrates EBV's mastery of navigating the complexities of the immunological landscape. Further investigation into these complex mechanisms is imperative to advance the development of enhanced therapeutic approaches with heightened efficacy. This review provides a comprehensive overview of various mechanisms known to date, employed by the EBV to elude the immune response, while establishing enduring latent infections or instigate its lytic replication.

[Epstein-Barr virus-associated gastritis with perigastric lymphadenopathy accompanied by infectious mononucleosis:a case report].

A 28-year-old female patient with no particular medical history had a sore throat seven days before admission. Subsequently, she developed malaise, right abdominal pain, and a fever of 38°C and visited our hospital. A blood test revealed a mild inflammatory response and elevated liver enzymes, and she was admitted to the hospital for detailed examination and acute liver injury treatment. Various viral tests and autoantibody measurements revealed elevated Epstein-Barr virus (EBV) immunoglobulin M and negative EB nuclear antigen antibodies. Therefore, she was diagnosed with primary infectious mononucleosis-associated EB viral hepatitis. Abdominal computed tomography upon admission revealed swollen lymph nodes around the stomach;thus, esophagogastroduodenoscopy (EGD) was performed. A histopathological examination revealed severe lymphocytic infiltration, and EB encoding region in situ hybridization demonstrated that 10-20% of the lymphocytes were EBV-infected. Drip and rest treatment improved the patient's liver enzymes, and her symptoms resolved. Repeat EGD after two months revealed improved gastric erosions. Here, we report a case of EBV-associated gastritis that was discovered due to perigastric lymphadenopathy accompanied by infectious mononucleosis. This report includes a review of the literature because a few studies reported EBV-associated gastritis.

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.

Joint Flexibility and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After Mononucleosis.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease characterized by substantial fatigue, postexertional malaise, unrefreshing sleep, and orthostatic intolerance, among other symptoms. Specific risk factors for the development of ME/CFS have not been adequately characterized. It has been suggested that ME/CFS is a connective tissue disorder and that joint hyperflexibility is a risk factor for the development of ME/CFS. METHODS: The goal of this study was to examine whether joint hyperflexibility is a risk factor for the development of ME/CFS after infectious mononucleosis (IM). This study was part of a prospective cohort study. College students were studied for the development of IM and were followed up for the development of ME/CFS 6 months later. Participants in the cohort for the present study included 53 students who met criteria for ME/CFS 6 months after IM and 66 recovered control subjects who had modified Beighton scores (a measure of joint hyperflexibility) available. FINDINGS: No connection was found between joint hyperflexibility and the development of ME/CFS after IM. Differences in joint hyperflexibility (as measured by using the modified Beighton score) in the ME/CFS group and the control group were not statistically significant. Female subjects had significantly higher Beighton scores compared with male subjects. IMPLICATION: After IM, no relationship was found between joint hyperflexibility and the development of ME/CFS.

Modifiable risk factors for multiple sclerosis have consistent directions of effect across diverse ethnic backgrounds: a nested case-control study in an English population-based cohort.

BACKGROUND: Multiple sclerosis is a leading cause of non-traumatic neurological disability among young adults worldwide. Prior studies have identified modifiable risk factors for multiple sclerosis in cohorts of White ethnicity, such as infectious mononucleosis, smoking, and obesity during adolescence/early adulthood. It is unknown whether modifiable exposures for multiple sclerosis have a consistent impact on risk across ethnic groups. AIM: To determine whether modifiable risk factors for multiple sclerosis have similar effects across diverse ethnic backgrounds. METHODS: We conducted a nested case-control study using data from the UK Clinical Practice Research Datalink. Multiple sclerosis cases diagnosed from 2001 until 2022 were identified from electronic healthcare records and matched to unaffected controls based on year of birth. We used stratified logistic regression models and formal statistical interaction tests to determine whether the effect of modifiable risk factors for multiple sclerosis differed by ethnicity. RESULTS: We included 9662 multiple sclerosis cases and 118,914 age-matched controls. The cohort was ethnically diverse (MS: 277 South Asian [2.9%], 251 Black [2.6%]; Controls: 5043 South Asian [5.7%], 4019 Black [4.5%]). The age at MS diagnosis was earlier in the Black (40.5 [SD 10.9]) and Asian (37.2 [SD 10.0]) groups compared with White cohort (46.1 [SD 12.2]). There was a female predominance in all ethnic groups; however, the relative proportion of males was higher in the South Asian population (proportion of women 60.3% vs 71% [White] and 75.7% [Black]). Established modifiable risk factors for multiple sclerosis-smoking, obesity, infectious mononucleosis, low vitamin D, and head injury-were consistently associated with multiple sclerosis in the Black and South Asian cohorts. The magnitude and direction of these effects were broadly similar across all ethnic groups examined. There was no evidence of statistical interaction between ethnicity and any tested exposure, and no evidence to suggest that differences in area-level deprivation modifies these risk factor-disease associations. These findings were robust to a range of sensitivity analyses. CONCLUSIONS AND RELEVANCE: Established modifiable risk factors for multiple sclerosis are applicable across diverse ethnic backgrounds. Efforts to reduce the population incidence of multiple sclerosis by tackling these risk factors need to be inclusive of people from diverse ethnicities.

Infectious Mononucleosis: An Updated Review.

BACKGROUND: Infectious mononucleosis is common among adolescents and young adults. Although the majority of cases resolve spontaneously, life-threatening manifestations, and complications have been recognised. OBJECTIVE: The purpose of this article is to familiarize clinicians with the clinical manifestations, evaluation, diagnosis, and management of infectious mononucleosis. METHODS: A search was conducted in October 2022 in PubMed Clinical Queries using the key terms "infectious mononucleosis" OR "Epstein-Barr virus" OR "EBV". The search strategy included all clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the aforementioned search was used in the compilation of the present article. RESULTS: Infectious mononucleosis, caused by Epstein-Barr virus, most commonly affects adolescents and adults aged 15 to 24 years. Epstein-Barr virus is transmitted primarily in saliva. Infectious mononucleosis is characterized by a triad of fever, tonsillar pharyngitis, and lymphadenopathy. Fatigue may be profound but tends to resolve within three months. Periorbital and/or palpebral edema, typically bilateral, occurs in one-third of patients. Splenomegaly and hepatomegaly occur in approximately 50% and 10% of cases, respectively. A skin rash, which is usually widely scattered, erythematous, and maculopapular, occurs in approximately 10 to 45% of cases. Peripheral blood leukocytosis is observed in most patients; lymphocytes make up at least 50% of the white blood cell differential count. Atypical lymphocytes constitute more than 10% of the total lymphocyte count. The classic test for infectious mononucleosis is the demonstration of heterophile antibodies. The monospot test is the most widely used method to detect the serum heterophile antibodies of infectious mononucleosis. When confirmation of the diagnosis of infectious mononucleosis is required in patients with mononucleosis-like illness and a negative mono-spot test, serologic testing for antibodies to viral capsid antigens is recommended. Infectious mononucleosis is a risk factor for chronic fatigue syndrome. Spontaneous splenic rupture occurs in 0.1 to 0.5% of patients with infectious mononucleosis and is potentially life-threatening. Treatment is mainly supportive. Reduction of activity and bed rest as tolerated are recommended. Patients should be advised to avoid contact sports or strenuous exercise for 8 weeks or while splenomegaly is still present. Most patients have an uneventful recovery. CONCLUSION: Infectious mononucleosis is generally a benign and self-limited disease. Prompt diagnosis is essential to avoid unnecessary investigations and treatments and to minimize complications. Splenic rupture is the most feared complication. As avoiding exposure to EBV is almost impossible, the most effective way to prevent EBV infection and infectious mononucleosis is the development of an effective, safe, and affordable EBV vaccine that can confer life-long immunity.

Antimicrobials use and infection hospital contacts as proxies of infection exposure at ages 0-2 years and risk of infectious mononucleosis.

Infectious mononucleosis (IM) often results from late primary infection with Epstein-Barr virus (EBV). Exposure to EBV at ages 0-2 years from, e.g., siblings therefore protects against IM. Using Danish registers, we therefore followed children born in 1997 through 2015 from age 3 years for a hospital contact with an IM diagnosis as outcome with the number of antimicrobial prescriptions filled before age 3 years as a proxy of infection pressure and the main exposure in stratified Cox regressions. The main analyses used sibships as strata primarily to adjust for health-seeking behaviour with further possible adjustments for age, sex, calendar period and sibship constellation. In these analyses we followed 7087 children, exposed on average to 3.76 antimicrobials prescriptions. We observed a crude hazard ratio for IM per unit increase in cumulative antimicrobial use of 1.00 (95% confidence interval 0.99, 1.02), with similar results in adjusted analyses. The hypothesis that children with the largest use of antimicrobials at ages 0-2 years would subsequently have the lowest risk of IM within a sibship was not corroborated by the data. Furthermore, sibship-matched analyses provided no support for some common early-life immune system characteristics being predictive of IM.

Acute myositis secondary to Epstein-Barr virus in the absence of infectious mononucleosis with severe rhabdomyolysis.

SummaryRhabdomyolysis is characterised by muscle breakdown which causes myoglobin light chain release and can result in renal injury. While some of the most common causes of rhabdomyolysis are trauma related, others include toxins, autoimmune processes or viral aetiologies. We present the case of a 20s-year-old man, with no significant medical history, who presented to the emergency department with a 1-week history of weakness, myalgias, nausea, vomiting and subjective fevers. A review of systems and physical exam were otherwise unremarkable, including being negative for sore throat, dysphagia and lymphadenopathy. On presentation, the patient was noted to have dark urine with a creatine kinase value of 452 458 U/L and an elevated creatinine at 7.23 mg/dL. The patient denied any trauma or increased physical activity. His toxin screen and autoimmune workup were negative. The patient's serological workup was significant for acute Epstein-Barr virus (EBV) infection, without additional viral coinfection or mononucleosis. During his hospitalisation course, the patient was managed with supportive care including haemodialysis. The patient made a full renal recovery and was discharged with scheduled outpatient follow-up. This case highlights the recognition of an acute EBV infection causing rhabdomyolysis in the absence of mononucleosis or concomitant infection.

Epstein-Barr virus and host cell 3D genome organization.

The human genome is organized in an extremely complexed yet ordered way within the nucleus. Genome organization plays a critical role in the regulation of gene expression. Viruses manipulate the host machinery to influence host genome organization to favor their survival and promote disease development. Epstein-Barr virus (EBV) is a common human virus, whose infection is associated with various diseases, including infectious mononucleosis, cancer, and autoimmune disorders. This review summarizes our current knowledge of how EBV uses different strategies to control the cellular 3D genome organization to affect cell gene expression to transform normal cells into lymphoblasts.

Comparative study of biomarkers for the early identification of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in infectious mononucleosis.

BACKGROUND AND AIM: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and infectious mononucleosis (EBV-IM) share mimic symptoms in the early stages of childhood development. We aimed to examine the clinical features and laboratory indices of these two diseases in children and uncover unique indicators to assist pediatricians in identifying these diseases early. METHODS: We collected clinical data from 791 pediatric patients diagnosed with EBV-IM or EBV-HLH, compared the clinical traits and laboratory biomarkers presented in the two groups, and constructed predictive models based on them. RESULTS: Patients with EBV-IM had greater ratios of cervical lymphadenopathy, eyelid edema, and tonsillitis, whereas individuals with EBV-HLH were more likely to have hepatomegaly and splenomegaly. When using the criteria of interleukin (IL)-10 > 89.6 pg/mL, interferon (IFN)-γ > 45.6 pg/mL, ferritin > 429 µg/L, D-dimer > 3.15 mg/L and triglycerides > 2.1 mmol/L, the sensitivity was 87.9%, 90.7%, 98.1%, 91.1% and 81.5% to predict EBV-HLH, while the specificity was 98.4%, 96.3%, 96.5%, 94.1% and 80.6%, respectively. A logistic regression model based on four parameters (IL-10, ferritin, D-dimer, and triglycerides) was established to distinguish EBV-HLH patients from EBV-IM patients, with a sensitivity of 98.0% and a specificity of 98.2%. CONCLUSIONS: IL-10, IFN-γ, ferritin and D-dimer levels are significantly different between EBV-HLH and EBV-IM. Predictive models based on clinical signs and laboratory findings provide simple tools to distinguish the two situations.

Expression and Clinical Significance of Peripheral Blood IL-17A, IL-22, Tim-3, and gal-9 in Children with Infectious Mononucleosis.

To investigate the expression and clinical significance of peripheral blood interleukin (IL)-17A, IL-22, T cell immunoglobulin molecule-3 (Tim-3), and galectin-9 (gal-9) in children with infectious mononucleosis (IM) caused by the Epstein-Barr virus (EBV). Peripheral blood of 54 children with IM (case group) was collected and divided into a liver damage group and a non-liver damage group. During the same period, 20 healthy children were in the control group. IL-17A and IL-22 were measured by enzyme-linked immunosorbent assay. Real-time quantitative polymerase chain reaction was used to measure the mRNA expression of Tim-3 and gal-9. Their correlation with clinical indicators was then analyzed. The IL-17A expression level was higher in the case group than in the control group, while Tim-3, gal-9, and IL-22 were lower than those in the control group. Tim-3 was positively correlated with gal-9, but negatively correlated with IL-17A. Tim-3 and gal-9 were positively correlated with CD4+/CD8+ cells. Conversely, they were negatively correlated with CD3+, CD3+CD8+, white blood cell, lymphocyte (L), alanine transaminase (ALT), aspartate transaminase (AST), glutamyl transpeptidase (GGT), and lactate dehydrogenase (LDH). In the case group, IL-17A was positively correlated with L, GGT, and LDH, but negatively correlated with the natural killer (NK) cell count. IL-17A and IL-22 were positively correlated with CD3+, CD3+CD8+, ALT, and AST, but they were negatively correlated with the ratio of CD4+/CD8+. In the liver damage group, IL-17A, IL-22, CD3+, CD3+CD8+, immunoglobulin A (IgA), IgG, IgM, L, ALT, AST, GGT, LDH, and α-hydroxybutyrate levels were higher than those in the non-liver damage group. However, Tim-3, gal-9, the ratio of CD4+/CD8+, and NK were lower than those in the non-liver damage group. IL-17A, IL-22, Tim-3, and gal-9 are involved in the immune pathogenesis of IM caused by EBV infection in children, which may be related to immune liver injury.