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Background Hypertriglyceridemia can occur in lymphoproliferative disorders. Infectious mononucleosis is a self-limiting, benign lymphoproliferative disorder. This study aimed to investigate the serum triglyceride concentrations and their change over time in patients with infectious mononucleosis. Methods We evaluated an adult patient with severe hypertriglyceridemia (>1000 mg/dL) during infectious mononucleosis and reviewed the records of 360 patients admitted to our hospital because of infectious mononucleosis (median age, 19 years; range, 15-87 years; 51.4% male). We compared the serum triglyceride concentrations with those of a control sample from the general population (n=75). A second triglyceride measurement, obtained during convalescence (median of 30 days after the initial determination), was available for 160 patients. Results The triglyceride concentrations in the acute phase (median: 156 mg/dL) were significantly higher than those of the controls (median, 76 mg/dL; P150 mg/dL), which was more common in the patients older than 30 years than in the younger patients (78.6% vs. 50.6%; PPPP Conclusions Patients with severe infectious mononucleosis frequently show mild, transient hypertriglyceridemia. Further studies are needed to elucidate the mechanisms underlying this finding.

BackgroundThe pathogenesis of multiple sclerosis (MS) has not yet been fully uncovered. There is increasing evidence that Epstein-Barr-Virus (EBV) infection, which affects over 90% of people during life and causes infectious mononucleosis, leads to an increased incidence of MS, and thus may play a crucial role in the pathophysiology of the disease.MethodsUsing the Disease Analyzer database (IQVIA) featuring diagnoses as well as basic medical and demographic data of outpatients from general practices in Germany, we identified a total of 16,058 patients with infectious mononucleosis that were matched to a cohort of equal size without infectious mononucleosis based on patients’ age, sex, index year and yearly consultation frequency. Incidence of MS was compared within a 10-year follow-up period.ResultsWithin 10 years from the index date, the incidence of MS was 22.6 cases per 100,000 person-years among patient with infectious mononucleosis but only 11.9 cases per 100,000 person-years among individuals without infectious mononucleosis. In regression analysis, infectious mononucleosis was significantly associated with the incidence of MS (HR: 1.86, 95% CI: 1.09-3.16). Subgroup analysis revealed the strongest association between infectious mononucleosis and MS in the age group between 14 and 20 years (HR: 3.52, 95% CI: 1.00-12.37) as well as a stronger association in men compared to women.ConclusionInfectious mononucleosis is associated with an increased incidence of MS especially in younger individuals. Our data support the growing evidence of a decisive involvement of EBV in the currently unknown pathophysiology of MS and should trigger further research efforts to better understand and potentially prevent cases of this disabling disease in future.

Background Acute pancreatitis is a disorder of reversible inflammation of the pancreas. Only a few cases are related to infections and the most common pathogens are the viruses responsible for mumps, parotitis, and influenza. Epstein-Barr virus (EBV)-associated acute pancreatitis is a rare condition and it may occur in children and adults. Case presentation A 3-year-old female was admitted to the “G. Di Cristina” Children's Hospital in Palermo for vomiting and abdominal pain. Laboratory investigations revealed elevated amylase and lipase, with normal liver function tests. Abdominal ultrasound demonstrated an enlarged pancreas, with hypoechogenic areas; no biliary lithiasis was observed. Infectious disease serology was positive for the presence of EBV VCA IgM and IgG. A diagnosis of EBV-associated acute pancreatitis was made. The patient was treated conservatively and recovered. Conclusions Acute pancreatitis is rarely associated with EBV infection; a review of the English literature revealed only 10 pediatric and 6 adult cases. Patients with pancreatitis should always be evaluated for EBV serology, even in the absence of the typical clinical and hematological features of infectious mononucleosis. For these patients, good prognosis is generally expected.

BACKGROUND Common variable immunodeficiency (CVID) is a rare disease. Infectious mononucleosis-like symptoms due to Epstein-Barr virus reactivation in adulthood are also rare. Here, we aimed to report a case of Epstein-Barr virus reactivation presenting with relapsing infectious mononucleosis-like symptoms with liver failure in common variable immunodeficiency with chronic hepatitis B virus infection. CASE REPORT A 36-year-old Japanese woman with chronic hepatitis B virus infection developed relapsing fever, lymphadenopathy with marked splenomegaly, and ascites 6 months after treatment with propagermanium, a nonspecific immune modulator, and subsequent treatment with entecavir and pegylated interferon sequential therapy. Although the hepatitis B virus load was controlled, Epstein-Barr virus deoxyribose nucleic acid was detected in her serum. Seven months later, her symptoms improved following corticosteroid treatment. Prior to sequential therapy, she developed pneumonia 4 times in 2 months and exhibited consistent hypoimmunoglobulinemia before corticosteroid treatment. Further examinations showed low amounts of switched memory B cells, and absence or barely detectable levels of isohemagglutinins. Subsequently, she was diagnosed with common variable immunodeficiency. CONCLUSIONS Epstein-Barr virus reactivation with relapsing infectious mononucleosis-like symptoms can occur following immune modulation therapy in patients with common variable immunodeficiency, and this can affect the patient's primary disease. Therefore, immunoglobulin screening along with the consideration of CVID in all patients is required before immune modulation therapy is planned.

Epstein-Barr virus (EBV) is very common, with the infection rate in adults over 90% worldwide. Infectious mononucleosis (IM) is caused by primary infection with EBV. Most IM patients are generally considered to have a favorable prognosis, but a few patients will also develop complications. Children with severe symptoms will require hospitalization. However, the disease burden of children hospitalized with IM in China has been rarely described. In this study, we included the Face sheets of discharge medical records from 27 member children's hospitals of Futang Research Center of Pediatric Development from Jan 1st, 2016 to Dec 31st, 2020, and medical information such as gender, age, region, time of admission, length of stay and expenditure were extracted. There were 24,120 IM cases, which accounted for 0.42% (24,120/5,693,262) of all hospitalized cases during this period. The ratio of male to female was 1.48:1. Hospitalization for IM in the 4-6 ​years age group was the highest among inpatients of all age groups. Case numbers increased year by year between 2016 and 2020, and the monthly hospitalization was generally high from Jul to Sep but reduced from Jan to Feb per year. Bronchitis/pneumonia and hepatic dysfunction were two common complications in hospitalized IM patients. The median length of stay was 8 days, and the median cost of hospitalization was 970.59 US dollars. This study will help understand the epidemiological characteristics and disease burden of hospitalized children with IM in China.

Introduction Epstein-Barr Virus (EBV) has been previously reported to cause rare occurrence of mostly epithelial and nummular keratitis. We hereby report two patients developing bilateral peripheral deep interstitial keratitis following EBV-related infectious mononucleosis (IM). Description of cases Two female adolescents presented with findings of chronic relapsing posterior interstitial keratitis with neovascularisation mostly located in the superior and inferior peripheral cornea, in absence of signs of anterior uveitis. The disease presented months after the occurrence of IM. Other etiologies of interstitial keratitis were excluded. EBV DNA could not be detected in the aqueous humor of both patients. The patients responded promptly to topical corticosteroids, with multiple recurrences reported in one case. Conclusion EBV-induced IM can cause bilateral peripheral interstitial keratitis with delayed onset. Progressive relapsing course of the keratitis can be observed.

BACKGROUND: In Denmark, the acceptance of the HPV vaccination program has been threatened by reports of suspected adverse events. Epstein Barr Virus (EBV) infection is associated with symptoms of long-lasting tiredness and may be misinterpreted as HPV vaccine adverse events. The main aim of this study was to examine if EBV infection around time of HPV vaccination was a risk factor for later suspected vaccine adverse events.METHODS: The study was a nationwide register-based matched case-control study. Cases were females vaccinated against HPV in the period 2011 throughout 2017 with suspected adverse events. For each case, five HPV vaccinated females without suspected adverse events were selected. Information about EBV infection was obtained from the Danish Microbiology Database and assessed for three time periods: (1) before first HPV vaccination, (2) around time of HPV vaccination, and (3) any time during the study period 2010-2017. Multiple logistic regression was used to estimate the association between EBV and suspected adverse events.RESULTS: We identified 1217 cases, matched to 6085 controls. A higher proportion of cases (38; 3.1%) than controls (31; 0.5%) were tested for EBV around time of HPV vaccination and cases had elevated odds for testing both EBV positive (OR 4.52, 95% CI 2.68-7.63) and EBV negative (OR 20.99, 95% CI 5.81-75.79). Only five females were classified with acute/recent EVB infection in this period.CONCLUSION: Misinterpretation of EBV infection late symptoms is not a leading explanation for Danish females experiencing suspected adverse events after HPV vaccination. Although EBV cannot be excluded as an explanatory factor for a very small proportion of suspected adverse events, the findings are more likely explained by protopathic bias, i.e. the fact that a larger proportion of females suspecting adverse events are tested for EBV.

Epstein-Barr virus (EBV) is a human herpesvirus spread in childhood by contact with saliva. In all populations, the great majority of people are infected by middle age. EBV can cause asymptomatic infection, nonspecific symptoms or, especially in adolescents and young adults, the infectious mononucleosis (IM), characterized by pharyngitis, lymphadenopathy, fatigue, and fever. Two main types of skin rashes, accounted as atypical exanthems, occur in patients with acute IM: a faint erythematous maculopapular eruption of 24-48 hours duration (5-15% of the patients) or a pruritic maculopapular rash in almost all patients receiving ampicillin or amoxicillin. Moreover EBV acute infection has been related to other cutaneous manifestations, such as Gianotti-Crosti syndrome, unilateral laterothoracic exanthem (especially in children), and others. In this study, we reported a case of atypical exanthem with an erythematous-papulovesicular pattern in a 22-year-old female patient with IM and performed a review of the literature of the cutaneous and mucosal eruptions occurring during EBV acute infections.

Epstein-Barr virus (EBV) is the cause of infectious mononucleosis, which disproportionately affects university students. This population has the potential to benefit from a prophylactic EBV vaccine trial. Our objectives were to determine EBV infection status and associated demographic/lifestyle factors among first year undergraduate university students at the beginning and end of first year. EBV infection status was assessed by testing for circulating IgG class antibodies against EBV viral capsid antigen. Of 198 starting students; 56.1% were positive for EBV antibodies with a higher rate in women (64.8%) than men (41.1%); p=0.002. A history of deep kissing was associated with a higher rate of EBV antibody positivity. On follow-up 8 months later at the end of freshman year, 22.4% had acquired EBV antibodies for a primary infection incidence of 33.6/100 person years. These findings indicate that our first year undergraduate population contains sufficient EBV-naïve subjects for a prophylactic vaccine trial.

OBJECTIVE Epidemiological research in multiple sclerosis (MS) has mainly been performed in socioeconomically and ethnically limited populations; influences on MS risk have not been studied in prospectively collected non-White populations. We set out to study the influence of previously described MS risk factors in an ethnically diverse population. METHODS A nested case-control study was created using primary care records of >1 million individuals, >50% of whom identify as Black, Asian, and Minority Ethnic (BAME). MS cases were compared to an age- and sex-matched control cohort (1:4), and to a large unmatched cohort. Odds ratios (ORs) of disease were determined according to exposure of interest, and a multivariate model including all exposures was created. Potential pairwise interactions were considered where both indicated a significant effect. RESULTS A total of 1,344 confirmed MS cases were included. MS OR in blacks aged

Multiple sclerosis (MS) is a degenerative disease that affects 2.8 million people worldwide. It is a central nervous system disease (CNS), in which the myelin sheath covering the brain and spinal cord neurons is attacked. If the myelin sheath is damaged, a person can suffer permanent damage to the nerves. There are a number of factors that can increase a person’s risk of developing MS, such as obesity, smoking, vitamin D deficiency, certain tissue types (HLADRB1 ∗ 15 : 01) and infection with the Epstein–Barr virus (EBV). The latter virus can cause infectious mononucleosis, which can, in turn, result in lifelong infection in the host. To establish the relationship between MS and EBV, the author conducted a study on 1176 MS patients admitted to Saudi Arabia King Abdulaziz City centers. The researcher determined that MS occurred twice as much in females as it did in males, and also that EBV was much more widespread in MS female patients than MS male patients (27 : 1). Age was not a factor in the occurrence of EBV. There were limitations on data completeness and availability. Other trials using larger cohorts of patients are needed.

Epstein-Barr virus (EBV) is a herpes virus that mainly infects in B lymphocytes and occasionally reactivates lytically. Most individuals have been infected with EBV primarily in their childhood with no symptoms, and the virus persists latently for life. We have previously reported that EBV-infected B cells with thyrotropin receptor autoantibodies (TRAbs) on their surface [TRAb(+) EBV(+) cells] were present in the peripheral blood mononuclear cells (PBMCs) of healthy adult controls and patients with Graves' disease, and that TRAbs released in the culture medium of PBMCs containing TRAb(+) EBV(+) cells by EBV reactivation. EBV lytic reactivation induced the differentiation of host B cells into plasma cells and antibody production. Various autoantibodies have been detected during the acute phase of infectious mononucleosis (IM) that is the symptomatic primary infection of EBV. Therefore, the autoantibody production may be induced by the asymptomatic primary infection. In this study, we examined the presence of TRAb(+) cells, EBV(+) cells, and TRAb(+) EBV(+) cells in PBMCs from 29 healthy or subclinical children without Graves' disease and one cord blood that were divided into six age groups, and also measured plasma TRAb levels. The results obtained demonstrated that low levels of TRAb production occurred with EBV primary infection and lytic reactivation in children without symptoms of IM. Furthermore, the populations of TRAb(+) cells, EBV(+) cells, and TRAb(+) EBV(+) cells were small in the period of primary infection, but they potentially expand with repeated EBV lytic reactivation. This may partly explain why the onset of Graves' disease often occurs in young adults, but rarely in infancy.

The link between Epstein-Barr Virus (EBV) and breast cancer (BC) etiology remains unclear. We utilized the Health of Women (HOW) StudyThe HOW StudyA history of IM was associated with a lower likelihood of developing invasive BC compared to women who did not develop IM (adjusted OR = 0.83, 95% CI 0.72-0.94). That finding was driven by women who had IM between 10 and 22 years old (adjusted OR = 0.83, 95% CI 0.72-0.97) albeit no linear association between age at developing IM and breast cancer (p-trend 0.05). Women who had IM between 10 and 22 years old were less likely to develop estrogen receptor positive (ER+ ; adjusted OR = 0.84, 95% CI 0.71-0.99) or hormone receptor positive (HR+ ; adjusted OR = 0.86, 95% CI 0.73-1.01) BC. There was no association between IM and ER- or HR- BC.In the HOW Study

Background The risk of infectious mononucleosis (IM) is affected both by crowding and by sibship structure, i.e., number and signed age differential between an index child and a sibling. Siblings provide protection against IM by pre-empting delayed primary Epstein-Barr virus infection with its associated high risk of IM. The association between childcare attendance and risk of IM, on the other hand, has never been studied in a large, well-characterized cohort. Methods Danish children born in July 1992 through 2016 with a completely known simple childcare attendance history before age 1.5 years (n = 908,866) were followed up for a hospital contact with an IM diagnosis at ages 1.5–26 years. Hazard ratios (HRs) of IM for an additional year of exposure were obtained from stratified Cox regression analyses, stratified by sex and year of birth, with age as the underlying time scale, adjusted for sibship structure, and sociodemographic variables including parental ethnicity and maternal age. Results An additional year of exclusively attending a daycare home (max 5 children) yielded HR = 0.90 (95% confidence interval 0.81–1.00), and similarly, each year of exclusively attending a childcare institution (e.g., crèche) yielded HR = 0.94 (0.84–1.06). Conclusions Forwarding enrollment in childcare by a year lowers the risk of IM later in life much less than having an additional sibling of comparable age and has no practical public health implications. We find our results suggestive of a random threshold for successful Epstein-Barr virus infection that is more easily reached by a sibling than the collective of playmates in daycare homes or childcare institutions.

Key Points Question Is diagnosis of infectious mononucleosis (IM) in childhood or adolescence associated with subsequent development of multiple sclerosis (MS)? Findings In this population–based cohort study of 2 492 980 individuals in Sweden, IM in childhood and adolescence was associated with an increased risk of a subsequent MS diagnosis that remained significant after controlling for measured and unmeasured shared familial factors. Meaning These findings suggest that IM in childhood and particularly adolescence is a risk factor for a subsequent MS diagnosis, independent of shared familial factors, making it less likely that greater susceptibility to infection is the explanation., This cohort study assesses the association of hospital-diagnosed infectious mononucleosis in childhood and adolescence with risk of a multiple sclerosis diagnosis in young adults using national population registers in Sweden., Importance Epstein-Barr virus and its acute manifestation, infectious mononucleosis (IM), are associated with an increased risk of multiple sclerosis (MS). Whether this association is confounded by susceptibility to infection is still debated. Objective To assess whether hospital-diagnosed IM during childhood, adolescence, or young adulthood is associated with subsequent MS diagnosis independent of shared familial factors. Design, Setting, and Participants This population–based cohort study used the Swedish Total Population Register to identify individuals born in Sweden from January 1, 1958, to December 31, 1994. Participants aged 20 years were followed up from January 1, 1978, to December 31, 2018, with a median follow-up of 15.38 (IQR, 8.68-23.55; range, 0.01-40.96) years. Data were analyzed from October 2020 to July 2021. Exposure Hospital-diagnosed IM before 25 years of age. Main Outcomes and Measures Diagnoses of MS from 20 years of age were identified. Risk of an MS diagnosis associated with IM in childhood (birth to 10 years of age), adolescence (11-19 years of age), and early adulthood (20-24 years of age [time-dependent variable]) were estimated using conventional and stratified (to address familial environmental or genetic confounding) Cox proportional hazards regression. Results Of the 2 492 980 individuals (1 312 119 men [52.63%] and 1 180 861 women [47.37%]) included, 5867 (0.24%) had an MS diagnosis from 20 years of age (median age, 31.50 [IQR, 26.78-37.54] years). Infectious mononucleosis in childhood (hazard ratio [HR], 1.98; 95% CI, 1.21-3.23) and adolescence (HR, 3.00; 95% CI, 2.48-3.63) was associated with an increased risk of an MS diagnosis that remained significant after controlling for shared familial factors in stratified Cox proportional hazards regression (HRs, 2.87 [95% CI, 1.44-5.74] and 3.19 [95% CI, 2.29-4.46], respectively). Infectious mononucleosis in early adulthood was also associated with risk of a subsequent MS diagnosis (HR, 1.89; 95% CI, 1.18-3.05), but this risk was attenuated and was not significant after controlling for shared familial factors (HR, 1.51; 95% CI, 0.82-2.76). Conclusions and Relevance These findings suggest that IM in childhood and particularly adolescence is a risk factor associated with a diagnosis of MS, independent of shared familial factors.

Amoxicillin Rash in Infectious Mononucleosis A 7-year-old girl presented with an itchy rash after 1 week of treatment with amoxicillin for pharyngitis. She had erythematous papules and macules on h...

Patient: Female, 17-year-old Final Diagnosis: Epstein-Barr virus infection Symptoms: Jaundice • malaise • right upper quadrant abdominal pain Medication: — Clinical Procedure: — Specialty: Gastroenterology and Hepatology • Infectious Diseases Objective: Rare coexistence of disease or pathology Background: Infectious mononucleosis secondary to Epstein-Barr Virus is a common infection in young adults. Infection usually involves a self-limiting course of fevers, sore throat, malaise, and myalgias. Transaminitis is a relatively common complication; clinical jaundice, however, is rare. This case report highlights an uncommon complication of Epstein-Barr Virus infection in which hepatocellular injury led to clinical jaundice as well as radiologic evidence of gallbladder pathology mimicking acute calculous cholecystitis. Case Report: A 17-year-old girl with no prior medical history presented to our Emergency Department 1 week after being diagnosed with infectious mononucleosis. She was hemodynamically stable and her physical exam was notable for scleral icterus with right upper quadrant tenderness and positive Murphy’s sign. Multiple imaging modalities performed showed gallbladder wall thickening without common bile duct dilatation. A hepatobiliary iminodiacetic acid (HIDA) scan showed evidence of hepatocyte dysfunction with normal gallbladder filling. The imaging results obtained in conjunction with her laboratory testing and active infectious mononucleosis infection confirmed the patient’s presentation was a result of her Epstein-Barr virus infection and did not require surgical intervention for cholecystectomy. Conclusions: This case report highlights a rare complication of Epstein-Barr Virus infection and demonstrates the utility of interpreting hepatic function testing in conjunction with relevant imaging modalities in cases of clinical jaundice. By doing so, we were able to conclude the patient’s gallbladder pathology was related to acute acalculous cholecystitis (AAC) and did not warrant surgical intervention. The patient was given supportive care measures and made a full recovery.

Background The diagnostic value of high fluorescent lymphocytes (HFLC) and smudge cells in diseases like sepsis has been confirmed. In this study, we explore the diagnostic value of HFLC and smudge cells for infectious mononucleosis (IM). Methods Sixty‐two IM patients, 67 healthy controls, 84 patients with upper respiratory tract virus infection, and 35 patients with malignant lymphoid diseases were enrolled. The complete blood counts and leukocyte differential counts are tested, and the smudge cells were manually counted. Results The value of HFLC% and smudge cells of the IM group were significantly higher than those of healthy controls and disease controls (p 2/100 nucleated cells, it can show better (AUC = 1.000). When the cutoff value of the HFLC% was 1.2%, it can effectively distinguish IM patients from upper respiratory tract virus infection patients (AUC = 0.934); when smudge cells >16/100 nucleated cells, it also has high differential diagnosis value (AUC = 0.913). In addition, the AUC of the combination HFLC% and smudge cells for the differential diagnosis can be increased to 0.968. The performance value of single HFLC% (AUC = 0.942) for distinguishing IM from malignant lymphoid diseases was better than smudge cells and combine index with the cutoff value of 0.4%. Conclusion HFLC% and smudge cells can be used as effective indicators in the early diagnosis and differential diagnosis of IM., HFLC% can be used for auxiliary diagnosis of IM, thereby saving time and reducing cost of smear and manual classification. HFLC% assists the diagnosis of IM with the following advantages. First, this indicator has high specificity and sensitivity for the diagnosis of IM, which can effectively avoid missed diagnosed. Second, HFLC%, as one of the blood routine indicators, can be obtained directly from the automatic blood analyzer. It does not increase additional economic burdens and manual operations. It has better adaptability and superiority, and can prompt clinical diagnosis and treatment earlier. In addition, when the number of smudge cells in the peripheral blood increases, the doctor should be alert to the possibility of IM.

BACKGROUND Infectious mononucleosis (IM), mainly caused by the Epstein-Barr virus, can result in prolonged symptoms. The objective of this study was to look at the length of sick leave, diagnosis of IM, treatment and comorbidities in a real-world setting in Germany. METHODS This retrospective, cross-sectional study used electronic medical record data from office-based practices in Germany and included patients with an initial confirmed diagnosis of IM between the 1 January 1 2016 and December 31 2018. Patients of working age (18-65 years) with statutory health insurance were included in order to look at the working population who would need a sick note for their employers in case of illness. RESULTS Epstein-Barr virus was the most common cause of IM in this population of 1,596 patients with an average age of 32 years. The majority of patients were women in all cohorts (~60%). Although CFS, myocarditis and thrombocytopenia were not recorded frequently around the index date, the occurrence did increase during the follow-up period. Around half of patients received antibiotics. About 62% of all patients were on sick leave for an average of 20 calendar days around the time of their IM diagnosis. Only 1% were still on sick leave after 6 months. CONCLUSIONS A small percentage of patients remained on continuous sick leave after 6 months, suggesting that the long-term effect of IM on the ability to work was minor in our cohort. However, patients could still be experiencing symptoms that influence their quality of life.

Background This study aimed to assess the host immune signatures associated with EBV infection and its clinical value in indicating the severity of children with acute infectious mononucleosis (IM). Methods Twenty-eight pediatric patients with IM aged 3–8 years were enrolled. The immune phenotypes and cytokine secretion capability of T cells were detected. Results The percentages and absolute numbers of CD3+ and CD8+ T cells were significantly increased in IM patients compared with HCs. The percentages of Naïve CD4+ and CD8+ T cells were decreased but with increased percentages of memory CD4+ and CD8+ T subsets. Our results showed the upregulation of active marker HLA-DR, TCR-αβ, and inhibitory receptors PD-1, TIGIT in CD8+ T cells from IM patients, which suggested that effective cytotoxic T cells were highly against EBV infection. However, EBV exposure impaired the cytokine (IFN-γ, IL-2, and TNF-α) secretion capability of CD4+ and CD8+ T cells after stimulation with PMA/ionomycin in vitro. Multivariate analysis revealed that the percentage of HLA-DR+ CD8+ T cells was an independent prognostic marker for IM. The percentage of HLA-DR+ CD8+ T cells was significantly correlated with high viral load and abnormal liver function results. Conclusion Robust expansion and upregulation of HLA-DR in CD8+ T cells, accompanied with impaired cytokine secretion, were typical characteristics of children with acute IM. The percentage of HLA-DR+ CD8+ T cells might be used as a prominent marker not only for the early diagnosis but also for indicating the severity of IM.

Background Infectious mononucleosis (IM) and mononucleosis-like illnesses are common viral infectious diseases which are often accompanied by a high fever, pharyngitis and lymphadenopathy in adults, although such infection in childhood is generally subclinical. Most cases of IM are caused by the Epstein–Barr virus (EBV) or Cytomegalovirus (CMV). However, it is difficult to diagnose IM only with subjective symptoms, and thus EBV and CMV are nearly indistinguishable in clinical practice. Case presentation A 20-year-old healthy Japanese woman had a 2-day history of high fever and consulted us. She had sex for the first time 6 months earlier. Her virus antibodies showed that she was infected with primary CMV. About 5 months later, she again experienced high fever and lymph node enlargement at the posterior cervical region. Her virus antibodies showed that she was infected with primary EBV at that time. Conclusion Herein, we report a healthy adult Japanese woman with primary EBV infection relatively soon after primary CMV infection. It is very interesting to compare the symptoms and/or clinical data after EBV and CMV infection in the same patient within a short period of time. Our patient was diagnosed based only on subjective symptoms, physical examination and laboratory data, without tests of such virus-related antibodies. Therefore, clinicians should bear in mind that primary EBV infection and/or primary CMV infection is possible when patients have symptoms such as high fever, pharyngitis and lymphadenopathy, even in healthy adults.

Background/purpose: Acute HIV infection is characterized by a high concentration of HIV RNA in the plasma and rapid depletion of the CD4 cell count. This multicenter, retrospective observational study aimed to characterize the manifestations of acuteHIV infection in Taiwan. Methods: Between 1 January 2012 and 31 December 2016, all patients aged 20 years or greater who presented with acute HIV infection were included. Demographic and clinical characteristics of the patients at diagnosis were collected. Baseline laboratory assessment included hemogram, CD4 count, plasma HIV RNA load (PVL), serologic markers of syphilis and hepatitis A, B, and C viruses, and serum biochemistry. Results: The proportion of acute HIV infection was 6.9% among the patients with newly diagnosed HIV infection during the study period. The most common presenting symptoms of acute HIV infection were fever, fatigue, and myalgia. The median PVL at diagnosis was 5.9 log10 copies/ml, and median CD4 count was 307 cells/mm3. A total of 68 patients (27%) had baseline CD4 count less than 200 cells/mm3. Multiple logistic regression analysis, showed that the baseline CD4 count (OR, 4.02; p = 0.013) and aspartate aminotransaminase levels (OR, 3.49; p = 0.002) were associated with high PVL (>5 log10 copies/ml); and high baseline PVL (OR, 2.64; p = 0.002) was associated with symptomatic acute HIV infection. Conclusions: Manifestations of acute HIV infection are nonspecific and of wide spectrum ranging from fever to severe illness. A higher proportion of patients with initial CD4 counts of 200 cells/mm3 or less during acute HIV infection warrants early, timely diagnosis and treatment to prevent rapid disease progression. Keywords: Acute HIV infection, Aseptic meningitis, Combination antiretroviral therapy, Fiebig stage, Infectious mononucleosis

Background:Infectious mononucleosis is typically a self-limited disease commonly affecting young adults. Splenic rupture is a rare but serious complication affecting 0.1% to 0.5% of patients with mononucleosis. Current guidelines (based on published case reports) recommend complete activity restriction for 3 weeks after onset of mononucleosis symptoms to reduce rupture risk. We examined actual timing of mononucleosis-associated splenic injury using a large repository of unpublished patient data.Hypothesis:The risk of splenic injury after infectious mononucleosis will remain elevated longer than previously estimated.Study Design:Retrospective case series.Level of Evidence:Level 4.Methods:The Military Health System Management Analysis and Reporting Tool (M2) was used to conduct a retrospective chart review. Coding records of TRICARE beneficiaries aged 5 to 65 years between 2006 and 2016 were screened. Patients diagnosed with both splenic injury and mononucleosis-like symptoms were identified, and their medical records were reviewed for laboratory confirmation of infection and radiographically evident splenic injury.Results:A total of 826 records of splenic injury were found in M2. Of these, 42 cases met the study criteria. Mean time to splenic injury was 15.4 (±13.5) days. Only 73.8% (n = 31) of injuries occurred within 21 days, and 90.5% (n = 38) of splenic injuries occurred within 31 days of symptom onset.Conclusion:A substantial number of splenic injuries occur between 21 and 31 days after symptom onset. While most splenic injuries were atraumatic, consideration should be given to extending return-to-play guidelines to 31 days after symptom onset to minimize risk. Risk of chronic pain after splenic injury may be higher than previously believed.Clinical Relevance:The risk for postmononucleosis splenic injuries remains elevated longer than current guidelines suggest. Restricting activity for 31 days after mononucleosis symptom onset may reduce the risk of splenic injury.

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.

INTRODUCTION 3D-DIFF scattergram of the Mindray BC-6800 haematological analyser shows morphological abnormalities and lymphocyte cluster splitting related to the presence of reactive lymphocytes. This study aims to assess whether these cytographic changes are useful in detecting both activated and apoptotic lymphocytes, leading to an improvement in the laboratory diagnostic process of infectious mononucleosis. METHODS Two hundred three samples with modified shape and doubled lymphocyte cluster of DIFF scattergram (study group) were divided into two different subgroups: with and, respectively, without serological evidence of ongoing IM. Activated and apoptotic cells in peripheral blood were counted by light microscopy or gating in the instrumental dot plots. Values of apoptotic cells counted by microscopy were compared with those resulting from gating. RESULTS Samples with both shape change and doubled lymphocyte cluster had serological profiles according to the diagnosis of ongoing infectious mononucleosis. Blood smears review was positive for reactive lymphocytes in all 112 samples (100%). An underestimation of apoptotic cell count by light microscopy compared with the gating in the instrumental scatterplot was also observed (96 out of 112, 85.7%). CONCLUSION The additional lymphocyte cluster was significantly associated with activated and apoptotic lymphocytes in samples with serology suggesting ongoing infectious mononucleosis. Considering the significance of clue for infectious mononucleosis assigned to the apoptotic lymphocytes, a specific flag such as "apoptotic cells?" could be associate with the related cluster. Such a flag could be used for dedicated rules for smears review, thus increasing infectious mononucleosis detection in laboratories that do not usually practise instrumental cytograms observation.

Objectives This study aimed to compare the clinical features and laboratory tests of infectious mononucleosis (IM) and hemophagocytic syndrome (HLH) caused by Epstein-Barr virus (EBV) in 1–3-year-old children and to explore the risk factor of HLH caused by EBV (EBV-HLH). Methods The clinical data of 92 children with EBV infection admitted in our hospital from 2011 to 2019 were collected; 61 cases were diagnosed as EBV-IM, and 31 cases were diagnosed as EBV-HLH. The subjects’ clinical manifestations and laboratory tests were analyzed retrospectively. Results Compared with EBV-IM patients, EBV-HLH patients had longer durations of fever, both before hospitalization and overall, and a higher probability of hepatomegaly. The levels of ALT, AST, LDH, TG, SF, D-Dimer and the plasma EBV DNA load of EBV-HLH patients were significantly higher than those of EBV-IM patients. The absolute values of CD3+, CD4+, CD8+, NK, and CD3-CD19+ cells and IgA and IgM levels of EBV-HLH patients were significantly lower than those of EBV-IM patients. The plasma EBV DNA load was positively correlated with the PT, TT, α-HBDH, AST, LDH, CK, Scr, BUN, UA, TG, and CRP levels in EBV-HLH patients, and the plasma EBV DNA load was positively correlated with the D-Dimer level in the EBV-IM patients. Among the 10 different potential markers, at the cut-off point of 1721.500 μg/L, the sensitivity and specificity of D-Dimer was 88.90 and 90.20%, respectively. Conclusion The D-Dimer level may be a good prognostic indicator of EBV-HLH caused by EBV.

BackgroundEpstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics.MethodsPatients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively.ResultsBroad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group.ConclusionPatients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months.Clinical Trial Registrationhttps://clinicaltrials.gov/, identifier NCT02335437.

To study the clinical features of infectious mononucleosis (IM) caused by Epstein-Barr virus (EBV) mixed with Mycoplasma pneumonia (MP) or/and cytomegalovirus (CMV)infection, collected 201 hospitalized children who met the IM diagnostic criteria, the clinical manifestations, laboratory tests, complications, treatment, and outcome were compared among EBV infection alone and EBV mixed with MP or/and CMV infection. Most of the children with IM were preschoolers, more frequently occurred in boys than girls. EBV patients with MP had the longest duration of fever. When mixed pathogen infections were involved, the white blood cell count of preschool children was significantly increased, while splenomegaly was more common in older children. In the cases of EBV infection alone, abnormal liver function was positively correlated with age ( P = 0.044 ). Mixed pathogen infections were more common in children with IM, occurring in all age groups, and some clinical characteristics were related to the age of onset and the pathogen of the infection.

Epstein-Barr virus infection is common, with seroprevalence of 90% in adults. Clinical presentation of primary EBV infection can be variable and atypical. It is often subclinical or can result in infectious mononucleosis. Clinical course is mostly benign, but in rare cases serious short- and long-term complications may occur.We present a case of a 19-year-old woman who was admitted to the hospital with general malaise, fever, dyspnea, icterus, vomiting and diarrhea, with acute left upper quadrant pain. She was diagnosed with acute EBV-infection with hepatitis, splenomegaly and spontaneous splenic rupture.Spontaneous splenic rupture is an uncommon, but potentially fatal complication of infectious mononucleosis. In a patient with suspicion of EBV infection and abdominal pain, we should always be aware of the possibility of spontaneous splenic rupture and emphasis should be put on appropriate counseling.

Objective To investigate the clinical manifestations of infectious mononucleosis in children of different ages. Methods Clinical data from pediatric patients with infectious mononucleosis admitted from May 2015 to April 2019 were retrospectively analyzed. Patients were stratified into three groups (age 1–3 years, 4–6 years, and 7–14 years) for analysis of clinical and laboratory results. Results Data from 61 patients (male:female ratio 1.18:1) aged 5.15 ± 2.93 years (mean ± standard deviation; range: 1–14 years) were analyzed. Infectious mononucleosis occurred throughout the year and the main clinical manifestations were fever (98.3%), tonsillitis (100%), tonsillar white exudate (83.6%), cervical lymphadenopathy (98.3%), hepatomegaly (37.7%), splenomegaly (42.6%), eyelid edema (41.0%), and nasal obstruction (49.2%). Disease onset was most common during early childhood (37.7%) and at preschool age (37.7%). Younger children had more obvious symptoms of nasal obstruction and older children had more significant elevations of alanine aminotransferase and higher percentages of atypical lymphocytes. Conclusion The clinical manifestations of infectious mononucleosis in children differed by age. These associations required attention for clinical decision making.

Epstein-Barr virus (EBV)-based serologic antibody and viral nucleic acid assays have been found to be feasible means to diagnose infectious mononucleosis (IM) caused by EBV in children. In this study, we will further explore their diagnostic value for IM by EBV in different age stages and over the course of the disease. A collection of 616 children from clinically suspected IM cases was studied. Indirect immunofluorescence (IIF) for EBV-specific antibody (Euroimmun) combined with plasma EB viral nucleic acid assay (real-time fluorescence quantitative polymerase chain reaction reverse-transcription polymerase chain reaction) were used as reference methods. The diagnostic efficiency of the peripheral blood routine test, serologic antibody test, and plasma EB viral nucleic acid assay for the diagnosis of IM was evaluated, respectively. The sensitivity, specificity, Youden' index and the area under curve (AUC) were 93.08%, 87.77%, 0.81 and 0.904 (95% confidence interval [CI]: 0.878-0.931) for the peripheral lymphocyte test (lymphocytosis > 5 × 109 /L), 98.27%, 91.13%, 0.89 and 0.947 (95% CI: 0.927-0.967) for the plasma EBV-DNA test, and 84.08%, 96.33%, 0.80 and 0.902 (95% CI: 0.874-0.930) for the EBV viral capsid antigen (VCA)-IgG avidity test. The plasma EBV-DNA test has a higher diagnostic value than the VCA-IgG avidity test in children aged

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and activate innate and adaptive immune responses. Single nucleotide polymorphisms (SNPs) within the TLR genes may influence host–pathogen interactions and can have an impact on the progression of infectious diseases. The present study aimed to investigate the genotype distribution of TLR2 (2029C/T, rs121917864; 2258G/A, rs5743708), TLR4 (896A/G, rs4986790), and TLR9 (− 1237T/C, rs5743836; − 1486T/C, rs187084; 1174G/A, rs352139; and 2848C/T, rs352140) polymorphisms in 149 children and adolescents with infectious mononucleosis (IM) and 140 healthy individuals. The potential association of TLR SNPs with the clinical manifestations of EBV infection was also studied. The presence of TLR2, TLR4, and TLR9 SNPs was identified by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). EBV DNA loads were detected by quantitative real-time PCR assay. The TLR4 896 GG and the TLR9 1174 GA genotypes were associated with an increased risk of EBV-related IM in examined patients (p = 0.014 and p = 0.001, respectively). The heterozygous genotype of the TLR4 896A/G SNP was associated with an increased risk of elevated liver enzyme levels and leukocytosis (p TLR4 896A/G and the TLR9 1174G/A polymorphisms seem to be related to the course of acute EBV infection in children and adolescents.

Splenic rupture is a rare but potentially fatal complication of infectious mononucleosis. We report the case of an 18-year-old woman, who presented a 7-day history of abdominal pain, sudden temporary loss of consciousness and fever. Admission blood tests showed anemia, and lymphocytosis. Computed tomography of the abdomen and pelvis demonstrated extensive hemoperitoneum and numerous cervical, mesenteric and inguinal enlarged lymph nodes. Laparoscopy was performed and abundant hemoperitoneum with blood clots along the left parietocolic gutter were observed. The spleen was completely decapsulated and surrounded by a hematoma and the subcapsular tissue was bleeding. Total splenectomy was performed without complications. Splenic histology demonstrated white pulp attenuation and expansion of the red pulp with focal hemorrhage and necrosis. IgM anti-viral capsid antigen of Epstein Barr virus was positive. The patient had a satisfactory recovery.

MiR-BART16 is a newly discovered Epstein-Barr Virus-encoded microRNA (miRNA). We aimed to explore the role of EBV-miR-BART16 in infectious mononucleosis (IM).Peripheral blood lymphocyte subsets were analyzed in 30 IM and 10 healthy children by flow cytometry. MiR-BART16 and its targets were measured by real-time PCR, western blot, ELISA, and dual-luciferase assay.Serum miR-BART16 expression was significantly higher in the IM children than that in the healthy children, and was positively correlated with EBV copy number. Receiver operating characteristic analysis revealed serum miR-BART16 could differentiate IM and healthy individuals (These results highlight that EBV-miR-BART16 plays an important role in regulating the expression of CAND1 to affect pediatric IM.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but potentially life-threatening complication, frequently associated with Epstein-Barr virus (EBV), which develops after solid organ or stem cell transplantation. Immunosuppression received by transplant recipients has a significant impact on the development of PTLD by suppressing the function of T cells. The preferential proliferation of NKG2A-positive natural killer (NK) cells during primary symptomatic EBV infection known as infectious mononucleosis (IM) and their reactivity toward EBV-infected B cells point to a role of NK cell in the immune control of EBV. However, NK cell-mediated immune response to EBV in immunosuppressed transplant recipients who develop PTLD remains unclear. In this study, we longitudinally analyzed the phenotype and function of different NK cell subsets in a cohort of pediatric liver transplant patients who develop PTLD and compared them to those of children with IM. We found persistently elevated plasma EBV DNA levels in the PTLD patients indicating suboptimal anti-viral immune control. PTLD patients had markedly decreased frequency of CD56dimNKG2A+Killer Immunoglobulin-like receptor (KIR)− NK cells from the time of diagnosis through remission compared to those of IM patients. Whilst the proliferation of CD56dimNKG2A+KIR− NK cells was diminished in PTLD patients, this NK cell subset maintained its ability to potently degranulate against EBV-infected B cells. Compared to cytomegalovirus (CMV)-seropositive and -negative IM patients, PTLD patients co-infected with CMV and EBV had significantly higher levels of a CMV-associated CD56dimNKG2ChiCD57+NKG2A−KIR+ NK cell subset accumulating at the expense of NKG2A+KIR− NK cells. Taken together, our data indicate that co-infection of CMV and EBV diminishes the frequency of CD56dimNKG2A+KIR− NK cells and contributes to suboptimal control of EBV in immunosuppressed children with PTLD.

There are few studies on sex difference in patients with infectious mononucleosis caused by Epstein-Barr virus (EBV-IM). We performed a retrospective study to evaluate the sex difference in clinical presentation of patients with EBV-IM.We performed a single-center retrospective study evaluating14-year-old patients with serologically confirmed EBV-IM during 2006-2017. We compared the patients' age, symptoms, physical findings, and laboratory data between male and female patients. To adjust for confounding factors, we performed a logistic regression analysis based on the results of univariate comparisons.Of the 122 eligible patients (56 male and 66 female, ratio: 1:1.2), the median ages were 26 years old (interquartile range [IR], 22-31.5 years old]) and 22 years old (IR, 20-25 years old) for males and females, respectively (p 0.001). Headache was significantly more prevalent in males (25.0% vs. 10.6%, p = 0.036). Leukocyte count was also significantly higher in males (11,400/mmOur single-center retrospective study suggests that older age of onset, headache, and leukocytosis are more likely to be characteristics of male patients with EBV-IM. Our study also underscores the importance of periorbital edema as a clue for early diagnosis of EBV-IM, especially in female patients.

Objective Because obesity affects the cellular immune response to infections, we aimed to investigate whether high body mass index (BMI) in young adulthood and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels interact with regard to MS risk. We also aimed at exploring potential 3-way interactions between BMI at age 20 years, aspects of Epstein-Barr virus (EBV) infection (high EBNA-1 antibody levels and infectious mononucleosis [IM] history, respectively) and the human leukocyte antigen (HLA)-DRB1*15:01 allele. Methods Using Swedish population-based case-control studies (5,460 cases and 7,275 controls), we assessed MS risk in relation to interactions between overweight/obesity at age 20 years, IM history, EBNA-1 levels, and HLA-DRB1*15:01 status by calculating ORs with 95% CIs using logistic regression. Potential interactions were evaluated on the additive scale. Results Overweight/obesity, compared with normal weight, interacted significantly with high (>50th percentile) EBNA-1 antibody levels (attributable proportion due to interaction 0.2, 95% CI 0.1–0.4). The strength of the interaction increased with higher category of EBNA-1 antibody levels. Furthermore, 3-way interactions were present between HLA-DRB1*15:01, overweight/obesity at age 20 years, and each aspect of EBV infection. Conclusions With regard to MS risk, overweight/obesity in young adulthood acts synergistically with both aspects of EBV infection, predominantly among those with a genetic susceptibility to the disease. The obese state both induces a chronic immune-mediated inflammation and affects the cellular immune response to infections, which may contribute to explain our findings.

Background The association between childhood vaccinations and infections and risk of multiple sclerosis is unclear; few studies have considered age at vaccination/infection. Objective To explore age-related associations between childhood vaccinations, infection and tonsillectomy and risk of a first clinical diagnosis of CNS demyelination. Methods Data on case (n=275, 76.6% female; mean age 38.6 years) and age- and sex-matched control (n=529) participants in an incident population-based case-control study included self-reported age at time of childhood vaccinations, infections, and tonsillectomy. Conditional logistic regression models were used to calculate adjusted odds ratios (AOR) and 95% confidence intervals (CI). Results Poliomyelitis vaccination prior to school-age was associated with increased risk of a first clinical diagnosis of CNS demyelination (AOR=2.60, 95%CI 1.02–6.68), based on a very small unvaccinated reference group. Late (11–15 years) rubella vaccination (compared to none) was associated with lower odds of being a case (AOR=0.47, 95%CI 0.27–0.83). Past infectious mononucleosis at 11–15 years (AOR=2.84, 95%CI 1.0–7.57) and 16–20 years (AOR=1.92, 95%CI 1.12–3.27) or tonsillectomy in adolescence (11–15 years: AOR=2.45, 95%CI 1.12–5.35), including after adjustment for IM, were associated with increased risk of a first clinical diagnosis of CNS demyelination. Conclusions Age at vaccination, infection or tonsillectomy may alter the risk of subsequent CNS demyelination. Failing to account for age effects may explain inconsistencies in past findings.

The risk of developing multiple sclerosis (MS) increases (OR: 3.1) after infectious mononucleosis (IM). However, the nature of this link is obscure. We tested the hypothesis that IM might incur long-term sequelae, including low-key inflammatory activity, with characteristics of an MS endophenotype (or presymptomatic trait) and that assays of MS-relevant cyto-/chemokines in the cerebrospinal fluid (CSF) post-IM may show a trend in this direction.We selected seven CSF cytokines (IL-1b, IL-6, YKL-40, TNF-alpha) or chemokines (IL-8, CCL2, IP-10), representing pro-inflammatory factors previously associated with MS. We assayed the CSF levels of these seven cyto-/chemokines in healthy individuals with a median follow-up time of 10 years after serologically confirmed IM (post-IM group, n = 22), and in healthy controls without a history of IM (n = 19). A group of MS patients (n = 23) were included as reference.The CSF levels of IP-10, YKL-40, and CCL-2 were higher in the post-IM group than in our IM unexposed controls (P = .021, .049, .028). Seven of seven cyto-/chemokine assays showed a trend in the predicted direction (P of binomial ratio = .008). However, this trend was non-significant in a multivariate test (P = .22). A power analysis indicated that similar studies including a larger cohort would be numerically realistic.These results do not reject the hypothesis that the established epidemiological association between IM and MS results from a stepwise inflammatory propagation from IM sequelae to an MS endophenotype (or presymptomatic trait) in a proportion of IM patients, pending confirmation with adequate power.

BackgroundEpstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which ∼95% of the healthy population is infected. EBV infection has been implicated in a range of haematological malignancies and autoimmune diseases. Delayed primary EBV infection increases the risk of subsequent complications. Over recent decades, the age of primary EBV infection has become later, largely due to improved sanitation and living conditions.Methods and findingsFirst, we conducted a sero-epidemiological survey of healthy volunteers between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. 1982 of 2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased monotonically with age, and increased more among females than males during adolescence (ages 10 – 15). Second, we conducted a retrospective review of Hospital Episode Statistics to determine changes in Infectious Mononucleosis (IM) incidence over time. Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. We then conducted a large case-control study of 6306 prevalent IM cases and 1,009,971 unmatched controls extracted from an East London GP database to determine exposures associated with IM. Exposures associated with lower risk of IM were elevated BMI (Overweight OR 0.80 [0.75 to 0.86], obese OR 0.63 [0.57 to 0.70]), non-white ethnicity (Black OR 0.21 [0.18 to 0.23], Asian OR 0.14 [0.13 to 0.16], Other ethnicity OR 0.22 [0.19 to 0.25]), and a history of smoking (OR 0.87 [0.83 to 0.92]), whereas affluence was associated with a higher risk of IM (per increase in IMD decile OR 1.15 [1.13 to 1.17]. Finally, we used ELISA to determine antibody responses to common pathogens and vaccine antigens among EBV-seronegative individuals. EBV-seronegative donors did not display diminished serum antibody responses to pertussis, rubella, or varicella compared to EBV-seropositive donors.ConclusionsIn this study we make several important observations on the epidemiology of EBV infection in the UK. We find that overall EBV seroprevalence in the UK appears to have increased, and that the sharp increase in EBV seropositivity takes places earlier among females than males. We find that the incidence of IM requiring hospitalisation is increasing. We find that exposures associated with prevalent IM in a diverse population include white ethnicity, affluence, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and encountered pathogens do not seem to be diminished among EBV-seronegative individuals, which is a theoretical counter-argument to developing EBV vaccines. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.Key messages-Epstein-Barr Virus (EBV) is a ubiquitous virus which infects over 95% of the world’s population. The majority of infection is silent and without consequence. In a subset of individuals, EBV is thought to play a role in the pathogenesis of autoimmune disease and haematological cancers.-During childhood and adolescence, EBV seroprevalence increased monotonically with age from 0-5 (67.8% females, 72.0% males) to 20-25 (96.4% females, 95.5% males)-The incidence of Infectious Mononucleosis (IM) leading to hospital admission has increased over the past decade-Exposure associated with IM in a large, diverse East London cohort (n>1,000,000) were low BMI, never-smoking, white ethnicity, and affluence.

Introduction . The presence of etiologically unencrypted diagnoses in the structure of viral hepatitis determines the relevance of searching for other pathogens involved in liver pathology formation. The role of Epstein-Barr virus in the development of hepatitis was described in the scientific literature, but official statistics do not allow to assess its contribution to liver damage along with hepatitis B and C viruses. The purpose – to identify common and distinctive epidemiological features of viral hepatitis B (HB), C (HC) and infectious mononucleosis (IM). Material and methods . A retrospective epidemiological analysis of these nosologies incidence was carried out according to official statistics in 2009-2018 in the Russian Federation. Results and discussion . The multidirectional trends in the long-term dynamics of the incidence of IM, acute and chronic HB and HC and the presence of strong direct correlation between the acute and chronic HB and HC incidence were established. Distinctive features include disparity in epidemic process intensity in different age groups (prevalence of morbidity in children aged 1–2 and 3–6 years with IM and persons older than 18 years – with viral hepatitis). It is common for IM and HB and HC to involve the majority of urban population in the epidemic process, as well as children under the age of 1 year. The described differences are due to the action of transmission mechanisms specific to each infection. Conclusion . The results obtained in this study may serve as a basis for further study of the interaction of EpsteinBarr virus with hepatitis B and C viruses.

EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS, and immune reactivity toward EBV is higher in persons with MS, indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS stimulates an immunopathological response, causing bystander neural cell damage. To verify this, we need to identify the immune culprits responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus-infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology., Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). However, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS can stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique. Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus and influenza A virus) proteins, and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a positive, suggesting a cytotoxic phenotype, and stuck to EBV-infected cells. Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV contribute to inflammation causing CNS injury. IMPORTANCE EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS, and immune reactivity toward EBV is higher in persons with MS, indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS stimulates an immunopathological response, causing bystander neural cell damage. To verify this, we need to identify the immune culprits responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus-infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

The existing reports regarding the potential role of infections as well as antibiotic use in multiple sclerosis (MS) etiology are inconclusive.We aimed to investigate the association of viral infections as well as antibiotic use and the risk of developing MS.This was a population-based incident case-control study of 547 incident cases and 1057 general population controls obtained from 22 municipality areas of Tehran (7/8/2013-17/2/2015). Multiple logistic regression models were used to determine the adjusted associations.Overall antibiotic use for ≥14 days during 3 years before the index date, significantly decreased the odds of MS OR 0.69 (95%CI: 0.53-0.91, P = .008). The results were consistent for different types of antibiotics, including penicillin OR 0.50 (95%CI: 0.34-0.75, P = .001) and cephalosporins OR 0.25 (95%CI: 0.12-0.50, P .001). History of IM was associated with a more than 5fold increased risk of MS OR = 5.7 (95%CI, 1.28-25.37). There was no statistically significant association between any other single or cumulative number of viral infections with subsequent risk of MS (P .05).Considering the possibility of reverse causation, the results of this large case-control study suggest that use of antibiotics may be associated with a decreased risk of MS. However, viral disease other than infectious mononucleosis was not associated with MS risk.

The objective of the current study was to assess the serum level of interleukin 27 in children with mononucleosis and to compare the expression of this cytokine in the acute and chronic phase of the infection.The level of IL-27 was determined using commercial enzyme-linked immunosorbent assay (ELISA) kits (Diaclone SAS, Besancon, France). Other laboratory findings were determined using routine laboratory methods.Serum level of IL-27 was found to be significantly higher in children with mononucleosis in comparison with healthy subjects (almost a 4-fold increase, 15.7 vs. 4.2 pg/mL, p 0.001). It was also significantly higher in the acute phase compared to the chronic stage of the disease (more than a two-fold increase, 20.7 vs. 9.64 pg/mL, p 0.001). This cytokine positively correlated with ALT, AST, LDH activity and WBC count (R = 0.498, p 0.001; R = 0.586, p 0.001; R = 0.170, p 0.05, R = 0.329, p 0.05, respectively) in the whole study, and only with AST activity in the chronic phase subgroup (R = 0.684, p 0.05).In conclusion, this study shows that serum concentration of interleukin 27 in children with mononucleosis is increased, thus confirming the on-going inflammatory process. We also suggest that IL-27 can be a useful indicator to differentiate between the acute and chronic phase of the disease.