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Background: The incidence of infectious mononucleosis (IM) has increased in recent years, particularly in the pediatric population, and there are currently no specific drugs available, posing a threat to the lives and health of children worldwide. Although some results have been published, there is a lack of systematic review and summarization of current research., Methods: Based on screening criteria, literature on IM in children from 2000 to 2023 was retrieved from the Web of Science Core Collection. The included literature's indicators (country, institution, journal, author, keywords, and references) were analyzed and visualized using Citespace, VOSviewer software, and the Bibliometrix program package., Results: A total of 538 eligible publications were included in this study. The number of publications has been on an upward trend during this century, with great potential for future growth. The countries with the most publications are the USA and China, and Capital Medical University is the most contributing institution. Hjalgrim, Henrik and Cohen, Jeffrey, I are among the field's most influential authors and co-cited authors. Among the major journals, the JOURNAL OF MEDICAL VIROLOGY had the highest output and the JOURNAL OF INFECTIOUS DISEASES was the most frequently cited. The reference with the highest outbreak intensity was Ramagopalan, SV, LANCET NEUROLOGY, 2010. Through in-depth analysis of the keywords, we conclude that the characteristics of diagnosis and assessment of IM, the association of IM with other diseases, and interventions for IM are the current hot topics of research in the field and that the pathogenesis of IM due to EBV is a cutting-edge topic in the field. This study also analyzes the reasons for geographical research differences and proposes a new "increasing quantity-improving quality-integrating" cooperation model., Conclusion: This study's hotspots and frontiers reflect the current status and trends in pediatric IM, and these findings provide important insights to guide future research and optimize therapeutic strategies. In the future, there is a need to strengthen international collaboration and cooperation, conduct RCTs with large sample sizes, and promote the development of new drugs in mechanism research., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

Large diagnostic panels allow for pathogens with high or low likelihood of causing attributable illness to be tested simultaneously. Infectious mononucleosis (IM) due to primary infection with Epstein-Barr virus (EBV) is a common cause of acute febrile illness (AFI) in case series from high-income countries, though its contribution to AFI in tropical low-income settings is unclear. As part of a case-control study using multiplex quantitative polymerase chain reaction (qPCR) diagnostics, we set out to determine if primary EBV infection was an underrecognized cause of AFI in the Peruvian Amazon. Presence of EBV DNA in whole-blood samples was equally prevalent among febrile cases and afebrile controls (34.6% [247/714] versus 35.7% [248/695]) and was not correlated with classic IM symptoms. Given the clear lack of clinical significance of the whole-blood PCR results, additional testing was pursued to ascertain the true prevalence of IM among cases of AFI in this population. The presence of EBV DNA in plasma, a marker of active EBV-related processes, was detected in 7% (5/68). Anti-EBNA-1 IgG, a late marker of prior infection, was tested via ELISA and detected in 4/5 of the plasma-positive patients, thereby excluding an acute primary EBV infection in all but one patient. Infectious mononucleosis due to primary infection with EBV was not an important etiology of AFI in the Peruvian Amazon, despite high rates of initial test positivity.

Objective: Infectious mononucleosis (IM) or mono is typically caused by primary infection with Epstein-Barr virus (EBV) and may have a months-long, complicated course. We utilized population-based data to add to the limited literature on health care utilization following EBV infection., Methods: The Rochester Epidemiology Project includes medical records for ∼60% of residents living in 27 counties of Minnesota (MN) and Wisconsin (WI). Persons meeting a case definition of recent EBV infection from 1 January 1998 to 31 December 2021 were compared to three persons not meeting the definition, matched on case's sex, age, and index date. Emergency department (ED) visits and hospitalizations in the two groups were compared during 5-years' follow-up divided into three periods (short-term ≤3 months, mid-term >3 months-1 year, long-term >1-5 years). Adjusted hazard ratios (AHR) were estimated to account for the potential influence of confounding variables., Results: In total, 6,423 persons had a recent EBV infection and were matched to 19,269 comparators. The risk of an ED visit was significantly higher among cases in the short-term period (24.3% vs referents: 7.6%, p  <.001; AHR = 3.71, 95% CI = 3.41-4.03). Cases also had an increased risk of hospitalization in the short-term (5.2% vs 1.6%: referents, p  <.001; AHR = 3.53, 95% CI = 2.94-4.24). For ED visits but not hospitalization, the excess risk persisted into the mid-term follow-up period. Persons without a concurrent clinical diagnosis of IM continued to have an increased risk of hospitalizations up to 1 year after index date (AHR = 1.45, 95% CI = 1.09-1.91) and an increased risk of ED visits up to 5 years after the index date (AHR = 1.29, 95% CI = 1.14-1.46)., Conclusion: There is a substantial short- and mid-term increased risk of serious health care encounters associated with recent EBV infection. Mid- and long-term risks are increased in patients who do not have a concomitant diagnosis of IM.

Purpose: This study aimed to assess the long-term risks associated with a history of infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV). Specifically analyzing the potential increase in developing nasopharyngeal cancer (NPC) and lymphoma in patients with a history of IM and exploring the prevalence of other EBV-associated conditions., Materials and Methods: The Korean National Health Insurance Service (NHIS) database was utilized for a retrospective analysis, covering data from 2002 to 2021. A total of 25,582 IM patients and controls were included, with 1:1 propensity score matching. The study monitored outcomes, including lymphoma, NPC, gastric cancer, multiple sclerosis, and all-cause mortality., Results: Patients with a history of IM demonstrated a significantly higher incidence of lymphoma (hazard ratio [HR], 5.320; 95% confidence interval [CI], 3.208 to 8.820; p < 0.001) and NPC (HR, 7.116; 95% CI, 1.617 to 31.314; p=0.009) during the follow-up period compared with the control group. Additionally, the IM group showed an increased rate of all-cause mortality (HR, 2.225; 95% CI, 1.858 to 2.663; p < 0.001)., Conclusion: This study suggests that individuals with a history of IM have an elevated risk of developing lymphoma and NPC in South Korea, emphasizing the importance of vigilant follow-up and monitoring. The results advocate for heightened awareness and potential national monitoring policies to address the long-term health implications of EBV infection and to implement preventive measures.

Infectious mononucleosis (IM) is suspected to be associated with inflammatory bowel disease (IBD) development. Using a Danish nationwide cohort of people developing severe IM and their age-, sex-, and socioeconomic (SES) index-matched counterparts, we investigated the subsequent risk of IBD, Crohn's disease (CD), or ulcerative colitis (UC) development from 1977 to 2021. Among 39,684 severe IM patients we find a sex-, age-, and SES index-adjusted HR for IBD of 1.35 (95% CI: 1.22-1.49). This significantly increased risk was seen for both CD (HR: 1.56; 95% CI: 1.34-1.83) and to a lesser extent UC (HR: 1.23; 95% CI: 1.08-1.40) and remains following negative control matching with a cohort diagnosed with Chlamydia trachomatis infection (HR: 1.39; 95% CI: 1.01-1.91). Those with severe IM at 0-9 years had a particularly increased risk for CD (HR: 1.77; 95% CI: 1.26-2.49). Here we show an increased risk for IBD diagnosis following IM hospitalisation, indicating an association between severe EBV disease and later IBD development. Further exploration of the potential factors contributing to IBD susceptibility following EBV disease is warranted., (© 2024. The Author(s).)

Objective: To analyze the manifestations of infectious mononucleosis and its impact on liver function in children., Methods: This retrospective study analyzed clinical data from 695 children with infectious mononucleosis (IM) who were hospitalized at the Department of Pediatrics, Chengdu First People's Hospital between January 1, 2017, and December 31, 2022. They were analyzed into two groups according to whether their ALT was greater than 40 U/L. Demographic variables, clinical features, and laboratory findings were collected from medical records. Statistical analyses were performed using the Statistic Package for Social Science (SPSS) 26., Results: A total of 695 children with infectious mononucleosis (IM)(409 males and 286 females) were included in the study. The age distribution was 161 infants (<3 years), 357 preschoolers (3-7 years), and 177 school-aged children (≥7 years). After clinical recovery, 61 cases had elevated liver enzymes. Asynchronous changes in AST and ALT were present in 18 children. The highest proportion of fever onset (75.2%) occurred in infancy (P = .00). Elevated AST, lymphocyte percentage and WBCs, age in school age, uncomplicated myocardial injury these were the risk factors for the development of liver injury in children with infectious mononucleosis. P values were .00, .048, .021, .000 and .002, respectively. 95% CIs were 65., 2-315.52, 1.01-3.48, 1.18- 7.37, 2.57-13.52 and 1.79-13.35, respectively., Conclusions: The clinical features vary with sex and age. Children with IM who are school-aged, without myocardial injury, and have elevated WBC, lymphocyte percentage, and AST should be monitored for potential liver damage. Careful evaluation is necessary following clinical recovery to determine if vaccination is appropriate.

Background: Previous investigations into multiple sclerosis (MS) risk factors predominantly relied on retrospective studies, which do not consider different follow-up times and assume a constant risk effect throughout lifetime., Objective: We aimed to evaluate the impact of genetic and early life factors on MS diagnosis by employing a time-to-event analysis in a prospective cohort., Methods: We used the UK Biobank data, considering the observation period from birth up to 31 December 2022. We considered genetic risk, using a multiple sclerosis polygenic risk score (MS-PRS), and various early life factors. Tobacco smoking and infectious mononucleosis diagnosis were also considered as time-varying variables along the follow-up. Using a Cox proportional hazards model, we examined the associations between these factors and MS diagnosis instantaneous risk., Results: We analyzed 345,027 participants, of which 1669 had an MS diagnosis. Our analysis revealed age-dependent effects for sex (females vs males) and higher MS-PRS, with greater hazard ratios observed in young adults., Conclusion: The age-dependent effects suggest that retrospective studies could have underestimated sex and genetic variants' risk roles during younger ages. Therefore, we emphasize the importance of a time-to-event approach using longitudinal data to better characterize age-dependent risk effects., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2023. The Author(s).)

Objective: The pathogenesis of inflammatory bowel disease (IBD) has not been fully uncovered to date. Epstein-Barr-Virus (EBV) infection has recently been associated with the pathogenesis of multiple sclerosis, suggesting a general link between EBV and autoimmune diseases. However, data on an association between EBV and IBD have remained inconclusive. This study aims at evaluating an association between EBV and the development of IBD., Methods: This retrospective cohort study included 15 931 patients with and 15 931 matched patients without infectious mononucleosis from the Disease Analyzer database (IQVIA) between 2000 and 2018. Incidences of Crohn's disease and ulcerative colitis were evaluated using Cox regression models., Results: Within 5 years of the index date, the cumulative incidence of IBD was 124 and 90 cases per 100 000 person-years among patients with and without infectious mononucleosis, respectively (P = 0.040). In regression analyses, infectious mononucleosis was significantly associated with IBD [hazard ratios (HR), 1.35; 95% confidence interval (CI), 1.01-1.81]. Subgroup analyses revealed an association between infectious mononucleosis and Crohn's disease (HR, 1.93; 95% CI, 1.22-3.05) but not ulcerative colitis (HR, 1.03; 95% CI, 0.70-1.51). This association was strongest in patients between 14 and 20 years (HR, 4.50; 95% CI, 1.55-13.13) and was only observed in females (HR, 2.51; 95% CI, 1.39-4.53)., Conclusion: Infectious mononucleosis is significantly associated with an increased incidence of Crohn's disease but not ulcerative colitis, especially in young female patients. Our data support the hypothesis of a pathophysiological involvement of EBV in the development of Crohn's disease and should trigger molecular research to further dissect the pathophysiology of IBD., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Although various genetic and lifestyle-related risk factors have been identified, its pathophysiology has not yet been fully unravelled. While acute EBV infection in the setting of infectious mononucleosis can lead to acute hepatitis, the long-term hepatic sequelae of infectious mononucleosis are still poorly understood., Methods: This retrospective cohort study included 13,859 patients with and 13,859 matched individuals without infectious mononucleosis from the Disease Analyzer database (IQVIA). Multivariable Cox regression analyses were used to evaluate the association between infectious mononucleosis and NAFLD., Results: Within 10 years of the index date, 2.64% of patients with infectious mononucleosis and 1.78% of individuals without infectious mononucleosis had been diagnosed with NAFLD (p < .001). The incidence of NAFLD was 263.9 cases per 100,000 person-years among individuals with infectious mononucleosis and 164.5 cases per 100,000 person-years among those without. Multivariable regression analyses indicated that infectious mononucleosis was significantly associated with the incidence of NAFLD (HR: 1.73) both among women (HR: 1.73) and among men (HR: 1.70). In age-stratified analyses, the association between infectious mononucleosis and NAFLD was most pronounced for the groups aged between 41 and 50 years (HR: 2.94) and >50 years (HR: 2.68)., Conclusion: Infectious mononucleosis is significantly associated with the incidence of NAFLD in a large cohort from Germany. These findings suggest a pathophysiological involvement of EBV in the development of NAFLD and could stimulate research efforts to better understand the pathophysiology of this emerging global medical burden., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Fever is a common symptom in children with infectious mononucleosis (IM). However, the significance of the duration of a fever is poorly understood. This study aimed to analyze the risk factors for persistent fever in children with IM., Methods: Patients diagnosed with IM (aged <18 years; except those with concomitant hematological malignancies or tumor diseases) in a high-volume academic hospital in 2019 were reviewed from a prospectively maintained database. Children with transient fever (≤7 days) were compared with those with persistent fever (>7 days). The risk factors for persistent fever in children with IM were examined using binary logistic regression. Furthermore, the predictive ability of these risk factors was assessed and presented using a receiver operating characteristic (ROC) curve., Results: Of the 184 children included in this study, 131 (71.96%) belonged to the transient fever group and 53 (28.04%) belonged to the persistent fever group (median age: 49 and 64 months, respectively; p = 0.093). Statistical significance was observed in hepatomegaly, alanine aminotransferase level, blood triglyceride level, and blood Epstein-Barr virus polymerase chain reaction (EBV-PCR) copy number (all p < 0.05). Binary logistic regression revealed that high blood triglyceride level was the risk factor for persistent fever in children with IM. High blood triglyceride level predicted persistent fever duration with an area under the ROC curve of 0.73 and an optimal cutoff value of 1.315 mmol/L., Conclusion: High blood triglyceride level was the risk factor for persistent fever in children with IM. Thus, children with elevated levels of blood triglycerides need additional care. To diagnose IM, a blood EBV-PCR is more useful than a throat-swab EBV-PCR., (© 2023 Japan Pediatric Society.)

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., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Asma Alanazi.)

Background: The 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., Methods: Using 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., Results: Within 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., Conclusion: Infectious 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., Competing Interests: Author KK was employed by IQVIA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Loosen, Doege, Meuth, Luedde, Kostev and Roderburg.)

Background: The link between Epstein-Barr Virus (EBV) and breast cancer (BC) etiology remains unclear. We utilized the Health of Women (HOW) Study ® to understand the association between infectious mononucleosis (IM), a surrogate for EBV infection, and invasive BC., Methods: The HOW Study ® was a web-based survey of BC risk factors with > 40, 000 participants; 183 had IM at < 10 years old, 3, 654 had IM between 10 and 22 years old, 764 had IM at > 22 years old, and 17, 026 never developed IM. Of these 21, 627 women, 2093 had Stages I-III BC and 14, 143 were cancer-free. Binary logistic regression ascertained the association between IM and invasive BC risk by controlling for confounders., Results: A 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., Conclusion: In the HOW Study ® , women diagnosed with IM between the ages of 10 and 22 had a lower risk of developing invasive BC compared to women who never developed IM., (© 2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Objective: 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., Methods: EBV infection status was assessed by testing for circulating IgG class antibodies against EBV viral capsid antigen., Results: Of 198 starting students; 56.1% were positive for EBV antibodies with a higher rate in women (64.8%) than male (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., Conclusion: These findings indicate that our first year undergraduate population contains sufficient EBV-naïve subjects for a prophylactic vaccine trial.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) involves severe fatigue, unrefreshing sleep, and cognitive impairment, leading to functional difficulties; prior studies have not evaluated risk factors with behavioral and immune data collected before developing ME/CFS. Up to 5% of university students develop infectious mononucleosis (IM) annually, and 9-12% meet criteria for ME/CFS 6 months later. We sought to determine predictors of ME/CFS., Methods: We enrolled college students at the start of the school year (time 1), identified those who developed IM (time 2), and followed them for 6 months (time 3), identifying 3 groups: those who developed ME/CFS, severe ME/CFS (meeting >1 set of criteria), and who were asymptomatic. We conducted 8 behavioral and psychological surveys and analyzed cytokines at 3 time points., Results: 238 of the 4501 students (5.3%) developed IM; 6 months later, 55 of the 238 (23%) met criteria for ME/CFS and 157 (66%) were asymptomatic. 67 of the 157 asymptomatic students served as controls. Students with severe ME/CFS were compared with students who were asymptomatic at 3 time points. The former group was not different from the latter group at time 1 (prior to developing IM) in stress, coping, anxiety, or depression but were different in several behavioral measures and had significantly lower levels of IL-6 and IL-13. At time 2 (when they developed IM), the 2 ME/CFS groups tended to have more autonomic complaints and behavioral symptoms while the severe-ME/CFS group had higher levels of IL-12 and lower levels of IL-13 than the recovered group., Conclusions: At baseline, those who developed ME/CFS had more physical symptoms and immune irregularities, but not more psychological symptoms, than those who recovered., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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.

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., (© 2021 John Wiley & Sons Ltd.)

Background: Infectious mononucleosis is a clinical diagnosis characterized by fever, sore throat, lymph node enlargement and often prolonged fatigue, most commonly caused by Epstein-Barr virus infection. Previous studies have indicated that infectious mononucleosis can be followed by depression; however, large-scale studies are lacking. We used nationwide registry data to investigate the association between infectious mononucleosis and subsequent depression in this first large-scale study., Methods: Prospective cohort study using nationwide Danish registers covering all 1,440,590 singletons born (1977-2005) in Denmark by Danish born parents (21,830,542 person-years' follow-up until 2016); where 12,510 individuals had a hospital contact with infectious mononucleosis. The main outcome measures were a diagnosis of major depressive disorder (ICD-8: 296.09, 298.09, 300.4; ICD-10: F32) requiring hospital contact., Results: Infectious mononucleosis was associated with a 40% increased hazard ratio (HR) for a subsequent depression diagnosis in the fully adjusted model (HR: 1.40, 95% CI: 1.26-1.56;n = 358), when compared to unexposed individuals. The increased risk of being diagnosed with depression was significant to the periods one to four years after the infectious mononucleosis diagnosis (HR: 1.40, 95% CI: 1.17-1.67;n = 121) and ≥ five years (HR: 1.40, 95% CI: 1.22-1.61;n = 207). We did not find any differences according to age (p = 0.61) nor sex (p = 0.30)., Conclusion: In this largest study to date, infectious mononucleosis in childhood or adolescence was associated with an increased risk of a subsequent depression. Our findings have important clinical implications and identifies youth with infectious mononucleosis as a group at high risk of later depression in young adulthood., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: 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., Methods: We performed a single-center retrospective study evaluating >14-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., Result: 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/mm 3 [IR, 7,600-14,100/mm 3 ] vs. 9,400/mm 3 [IR, 6,600-11,600/mm 3 ], p = 0.021). The prevalence of periorbital edema (male: 3.6% vs. female: 18.1%, p = 0.012) and severity of transaminase elevation were significantly higher in females. The regression analysis evaluating clinical characteristics of male patients showed that age >30 years old, headache, and leukocyte >11,000/mm 3 had high odds ratios., Conclusion: Our 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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Epstein-Barr virus (EBV) infection is thought to play a central role in the development of multiple sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk., Objective: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk., Methods: Pubmed was searched using the terms 'multiple sclerosis' AND 'Epstein Barr virus', 'multiple sclerosis' AND EBV, 'clinically isolated syndrome' AND 'Epstein Barr virus' and 'clinically isolated syndrome' AND EBV. All abstracts were reviewed for possible inclusion., Results: A total of 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (attributable proportion due to interaction (AP) = 0.48, p  < 1 × 10 -4 ). Previous infectious mononucleosis (IM) was associated with increased odds ratio (OR) of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR = 2.76) but not low anti-EBV antibodies (OR = 1.16). No interaction between EBV and risk factors was found on a multiplicative scale., Conclusion: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

Objectives: 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., Materials and Methods: 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., Results: 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., Conclusions: 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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Epstein-Barr virus (EBV) infection is the causative agent of multiple diseases. EBV DNA in blood is a useful diagnostic marker of primary EBV infection and reactivation. This study aimed to provide epidemiological information on children with EBV-associated diseases identified by positive EBV DNA in Hangzhou, a city in East China. All children admitted to the Children's Hospital of Zhejiang University School of Medicine from 2010 to 2015 with suspected EBV-related diseases and serum EBV DNA tested by quantitative real-time polymerase chain reaction were included. Of the 10 470 children, 1205 were determined to have positive EBV DNA, and the positive rate was 11.5%. 15.8% (973 of 6162) of the illnesses of patients aged 1 to 7 years were caused by EBV as compared to that of 6.6% (179 of 2708) of children older than 7 years (P < .01) and 3.3% (53 of 1600) of of that of infants <1 year of age (P < .01). Among positive EBV DNA patients, 80.7% of EBV infections occurred in children at the age stage of 1 to 7 years. IM was the most common EBV-related disease, accounting for 75.7% of 581 hospitalized patients. Children aged 1 to 3 years were the age group most commonly hospitalized with EBV-IM (32.7% of the cohort) and EBV-hemophagocytic lymphohistiocytosis (HLH) (52.6%), while EBV-lymphoma was more common in children over 9-year old (58.3% of the cohort). The serum EBV-DNA load was much higher in patients with EBV-HLH than in patients with IM (P < .05). This is a large sample study, which revealed the epidemiological characteristics of children with EBV-associated diseases, including age, monthly and disease distribution., (© 2019 Wiley Periodicals, Inc.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Two types of Epstein Barr virus (EBV1/EBV2) have been shown to infect humans. Although their genomes are similar, the regions containing the EBNA genes differ. This study aimed to characterize the EBV genotypes of infectious mononucleosis (IM) cases in the metropolitan region of Belém, Brazil, from 2005 to 2016. A total of 8295 suspected cases with symptoms/signs of IM were investigated by infectious disease physicians at Evandro Chagas Institute, Health Care Service, from January 2005 to December 2016. Out of the total, 1645 (19.8%) samples had positive results for EBV by enzyme immunoassay and 251 (15.3%) were submitted to polymerase chain reaction (PCR) technique, using the EBNA3C region, in order to determine the type of EBV. Biochemical testing involving aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were also performed. EBV type was identified by PCR in 30.3% (76/251) of individuals; of those, 71.1% (54/76) were classified as EBV1, 17.1% (13/76) as EBV2, and 11.8% (9/76) as EBV1 + EBV2. The main symptoms/signs observed with EBV1 infection were cervical lymphadenopathy (64.8%, 35/54), fever (63%, 34/54), headache (20.4%, 11/54), arthralgia (20.4%, 11/54), and exanthema (18.5%, 10/54). EBV2 infection was detected in all but two age groups, with an average age of 24 years. The most common signs/symptoms of EBV2 were fever (76.9%, 10/13), average duration of 18 days, and lymphadenopathy (69.2%, 9/13). In contrast, EBV1 + EBV2 coinfections were more frequent in those aged five years or less (20.0%, 2/10). The symptoms of EBV1 + EBV2 coinfection included fever (66.7%, 6/9), and cervical lymphadenopathy and headache (33.3%, 3/9) each. The mean values of hepatic enzymes according to type of EBV was significantly different (p < 0.05) in those EBV1 infected over 14 years of age. Thus, this pioneering study, using molecular methods, identified the EBV genotypes in 30.3% of the samples, with circulation of EBV1, EBV2, and EBV1 + EBV2 co-infection in cases of infectious mononucleosis in the northern region of Brazil., (Copyright © 2020 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Epstein-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. Contemporaneous seroepidemiological data is needed to establish best approaches for successful vaccination strategies in the future., Methods: We conducted a sero-epidemiological survey using serum samples from 2325 individuals between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. Second, we conducted a retrospective review of Hospital Episode Statistics to examine changes in Infectious Mononucleosis (IM) incidence over time. 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., Results: 1982/2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased more rapidly in females than males during adolescence (age 10-15). Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. Exposures associated with an increased risk of IM were lower BMI, White ethnicity, and not smoking., Conclusions: We report that overall EBV seroprevalence in the UK appears to have increased, and that a sharp increase in EBV seropositivity is seen in adolescent females, but not males. The incidence of IM requiring hospitalisation is increasing. Exposures associated with prevalent IM in a diverse population include white ethnicity, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and commonly encountered pathogens do not appear to be diminished among EBV-seronegative individuals. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.

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 <40 years was 1.15 (95% confidence interval [CI] = 0.81-1.62) compared to whites. MS odds in BAME current (OR = 1.71, 95% CI = 1.24-2.31) and ex-smokers (OR = 2.83, 95% CI = 2.14-3.72) were considerably higher than in Whites (OR = 1.09, 95% CI = 0.88-1.34; OR = 1.44, 95% CI = 1.19-1.74, respectively). Prior infectious mononucleosis was associated with increased odds of MS in Blacks (OR = 4.94, 95% CI = 1.23-17.89). An increase in MS odds was seen in the least-deprived quintile (OR = 2.46, 95% CI = 1.40-4.24), but no effect across deprived quintiles was seen., Interpretation: This cohort provides novel data on factors potentially driving MS susceptibility in a diverse population, one-third of whom live in poverty. Environmental exposures have differential risk across ethnicity. ANN NEUROL 2020;87:599-608., (© 2020 American Neurological Association.)

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., Competing Interests: The authors declare no conflict of interest.

Background: Infectious mononucleosis (IM) is a common adverse presentation of primary infection with Epstein-Barr virus (EBV) in adolescence and later, but is rarely recognized in early childhood where primary EBV infection commonly occurs. It is not known what triggers IM, and also not why IM risk upon primary EBV infection (IM attack rate) seemingly varies between children and adolescents. IM symptoms may be severe and persist for a long time. IM also markedly elevates the risk of Hodgkin lymphoma and multiple sclerosis for unknown reasons. The way IM occurrence depends on age and sex is incompletely described and hard to interpret etiologically, because it depends on three quantities that are not readily observable: the prevalence of EBV-naϊve persons, the hazard rate of seroconverting and the attack rate, i.e. the fraction of primary EBV infections that is accompanied by IM. We therefore aimed to provide these quantities indirectly, to obtain epidemiologically interpretable measures of the dynamics of IM occurrence to provide etiological clues., Methods and Findings: We used joint modeling of EBV prevalence and IM occurrence data to provide detailed sex- and age-specific EBV infection rates and IM attack rates and derivatives thereof for a target population of all Danes age 0-29 years in 2006-2011. We demonstrate for the first time that IM attack rates increase dramatically rather precisely in conjunction to typical ages of puberty onset. The shape of the seroconversion hazard rate for children and teenagers confirmed a priori expectations and underlined the importance of what happens at age 0-2 years. The cumulative risk of IM before age 30 years was 13.3% for males and 22.4% for females. IM is likely to become more common through delaying EBV infection in years to come., Conclusions: The change in attack rate at typical ages of puberty onset suggests that the immunologic response to EBV drastically changes over a relatively short age-span. We speculate that these changes are an integrated part of normal sexual maturation. Our findings may inform further etiologic research into EBV-related diseases and vaccine design. Our methodology is applicable to the epidemiological study of any infectious agent that establishes a persistent infection in the host and the sequelae thereof., Competing Interests: The authors have declared that no competing interests exist.

Background: The evidence associating diet and risk of multiple sclerosis is inconclusive., Objective: We investigated associations between dietary patterns and risk of a first clinical diagnosis of central nervous system demyelination, a common precursor to multiple sclerosis., Methods: We used data from the 2003-2006 Ausimmune Study, a case-control study examining environmental risk factors for a first clinical diagnosis of central nervous system demyelination, with participants matched on age, sex and study region. Using data from a food frequency questionnaire, dietary patterns were identified using principal component analysis. Conditional logistic regression models ( n  = 698, 252 cases, 446 controls) were adjusted for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, race, education, body mass index and dietary misreporting., Results: We identified two major dietary patterns - healthy (high in poultry, fish, eggs, vegetables, legumes) and Western (high in meat, full-fat dairy; low in wholegrains, nuts, fresh fruit, low-fat dairy), explaining 9.3% and 7.5% of variability in diet, respectively. A one-standard deviation increase in the healthy pattern score was associated with a 25% reduced risk of a first clinical diagnosis of central nervous system demyelination (adjusted odds ratio 0.75; 95% confidence interval 0.60, 0.94; p  = 0.011). There was no statistically significant association between the Western dietary pattern and risk of a first clinical diagnosis of central nervous system demyelination., Conclusion: Following healthy eating guidelines may be beneficial for those at high risk of multiple sclerosis.

Introduction: It remains unclarified if bacterial co-infection is common in patients with infectious mononucleosis (IM) and acute tonsillitis and/or peritonsillar abscess (PTA). Recent studies suggest that Fusobacterium necrophorum is a prevalent pathogen in acute tonsillitis and PTA. We hypothesised that this anaerobe may play a significant role for the aggravated infection and the development of PTA among teenagers and young adults with IM., Methods: All patients with IM and clinical findings of acute tonsillitis or PTA admitted to our department in the 2001-2015 period were included in the study., Results: In total, 257 patients with IM and acute tonsillitis (n = 220) or PTA (n = 37) were included. Positive bacterial cultures were obtained in 28% of patients with AT and in 50% with PTA. The most prevalent bacterial findings were Group C/G streptococci (14%) among patients with acute tonsillitis and Staphylococcus aureus (22%) in patients with PTA. F. necrophorum was recovered in 9% and 2% of patients with acute tonsillitis and PTA, respectively., Conclusions: We were unable to substantiate a prevalent role for F. necrophorum in patients with IM and acute tonsillitis/PTA. S. aureus may play a role in PTA development in patients IM. The majority of our findings did not support the use of antibiotics in patients with IM, even in this selected group of patients with severe symptoms and a high risk of PTA., Funding: This work was funded by the Lundbeck Foundation (Grant number R185-2014-2482)., Trial Registration: The Danish Data protection Agency approved the project., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Infectious mononucleosis (IM) is an acute infectious illness characterized by swollen lymph nodes, fever, pharyngitis, fatigue, and head and body aches. This report describes the incidence rates, trends, and demographic correlates of IM among active component service members during 2002-2018. During the surveillance period, there were 23,780 incident cases of IM, resulting in an overall incidence rate of 104.2 cases per 100,000 person-years (p-yrs). The incidence of IM diagnoses was highest among the youngest age groups and decreased with increasing age. The rate of incident IM diagnoses was markedly higher among non-Hispanic white service members (123.4 per 100,000 p-yrs) compared to those in other race/ethnicity groups. The incidence of IM diagnoses among recruits (364.9 per 100,000 p-yrs) was 3.4 times that among other enlisted personnel (106.0 per 100,000 p-yrs) and 5.6 times that among officers (64.7 per 100,000 p-yrs). The incidence of IM diagnoses remained relatively stable during the surveillance period, at about 100 per 100,000 p-yrs. IM is not considered to be a serious illness; however, it can seriously impact availability for duty during the acute phase.

Background: The existing reports regarding the potential role of infections as well as antibiotic use in multiple sclerosis (MS) etiology are inconclusive., Objectives: We aimed to investigate the association of viral infections as well as antibiotic use and the risk of developing MS., Materials & Methods: 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., Results: 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)., Conclusions: 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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The Epstein-Barr virus (EBV) is a common virus in humans and the most common causative agent of Infectious Mononucleosis. EBV primary infection has recently risen in some countries and children below 2 years of age are highly susceptible. The clinical manifestations in children with EB virus infection involve multiple systems, causing severe illness, meaning attention should be paid during diagnosis and treatment. Objective:  This single institution based retrospective study was carried out with the aim of estimating the overall prevalence of EBV infection and identifying high-risk age group among children.  Methods: This study include total 253 patients under 15 years of age found to be  positive for EBV DNA by serum PCR who were admitted to the Pediatrics Department of Renmin Hospital,(Shiyan, China) during a 4-year period from 2014 to 2017. Patients were divided into three groups; 0-<4years, 4-<6years and 6-<15years. We then calculated the percentage and prevalence of EBV DNA-positive cases. Results: The yearly EBV prevalence rate was 4.99 per 1000 admissions in 2014, 6.97 per 1000 admissions in 2015, 10.42 per 1000 admissions in 2016, and 12.16 per 1000 admissions in 2017. Out of 253 EBV-positive cases, those under 4 years had the highest rate of EBV infection (74.7%). The rate drops to 11.06% in the 4-6 years group, and was 14.22% in the 6-15 years group. Those between 6 months and 1 year are those at the highest risk.  Conclusion: The rate of hospital admission of children due to EBV infection is increasing day by day. Children under 4 years of age are highly susceptible to infection and children of age between 6 months and 1 year are the high-risk group for EBV infection., Competing Interests: No competing interests were disclosed.

Objectives: To determine the risk factors for severe infectious mononucleosis (IM) occurrence in immunocompetent adults., Methods: We performed a multicenter, retrospective case series including immunocompetent adults presenting with confirmed IM between 2001 and 2011. Severe presentations were compared with uncomplicated presentations using Stata ®  9 software. The significance level was set at 5%., Results: In univariate analysis, age over 30 years (n=13 or 41.9% vs. n=5 or 12.8%; P=0.006), prior use of non-steroidal anti-inflammatory drugs (NSAIDs) (n=7 or 87.5% vs. n=1 or 12.5%; P=0.009), and smoking (n=13 or 68.4% vs. n=6 or 31.6%; P=0.013) were associated with severe IM onset. In multivariate analysis, only age over 30 years (OR=3.55; P=0.05) and prior use of NSAIDs (OR=15; P=0.05) remained associated with severe IM onset, without reaching significance level (P=0.05)., Conclusion: Our study confirmed that age over 30 years is a risk factor for severe IM onset. Prior use of NSAIDs also seems to be correlated with severe presentations. This new data needs to be confirmed in a prospective study., (Copyright © 2017. Published by Elsevier SAS.)

Background: Infectious mononucleosis (IM) and vitamin D deficiency are both risk factors for multiple sclerosis (MS)., Objective: We wished to establish if IM in the winter months when vitamin D levels are low may be a greater risk factor for MS than IM in the summer months., Methods: We identified all patients with MS diagnosed aged 16-60 in a large primary care database in the United Kingdom and matched each by age, sex, general practice and observation period with up to six controls. We identified a coded diagnosis of IM prior to the index date (date of diagnosis). Logistic regression was used to calculate the odds ratio for prior IM exposure in cases versus controls and for winter versus summer exposure in cases and controls with prior IM exposure., Results: Based on 9247 cases and 55,033 matched controls (246 and 846 with prior IM respectively), IM was associated with the development of MS (OR 1.77, 95%CI 1.53-2.05) but there was no evidence that IM in the winter as opposed to summer was associated with developing MS (OR 1.09, 95%CI 0.72-1.66)., Conclusion: We found no evidence that the season of IM influences the risk of subsequent MS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Results from previous studies on a possible interaction between smoking and Epstein-Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting., Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS., Methods: Within the case-control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale., Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66-1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): -0.98, 95% CI: -2.05-0.15, p = 0.09)., Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.

Background: There has been substantial evidence accumulating on the role of infectious mononucleosis (IM) and the subsequent risk of obtaining Multiple Sclerosis (MS). Up to date studies not previously explored were reviewed by the author to further clarify the association., Methods: Medline and Web of Science were searched with no time constraints for articles exploring an association between Multiple Sclerosis and Infectious Mononucleosis. 24 articles were found, totalling 1063 cases and 13,227 cohort/controls., Results: 23/24 (96%) articles reported a significant association of Infectious Mononucleosis on the risk of subsequent multiple sclerosis., Discussion: Overall, new literature on IM and risk of MS categorically supports the association. Future work should focus on other risk factors such as age and gender on IM and subsequent risk of MS., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Epstein-Barr virus (EBV) primary infection is usually asymptomatic, but it sometimes progresses to infectious mononucleosis (IM). Occasionally, some people develop chronic active EBV infection (CAEBV) with underlying immunodeficiency, which belongs to a continuous spectrum of EBV-associated lymphoproliferative disorders (EBV + LPD) with heterogeneous clinical presentations and high mortality. It has been well established that T cell-mediated immune response plays a critical role in the disease evolution of EBV infection. Recently, high-throughput sequencing of the hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (T cell receptor β (TCRβ)) has emerged as a sensitive approach to assess the T cell repertoire. In this study, we fully characterized the diversity of peripheral blood TCRβ repertoire in IM (n = 6) and CAEBV patients (n = 5) and EBV-seropositive controls (n = 5). Compared with the healthy EBV-seropositive controls, both IM and CAEBV patients demonstrate a significant decrease in peripheral blood TCRβ repertoire diversity, basically, including narrowed repertoire breadth, highly expanded clones, and skewed CDR3 length distribution. However, there is no significant difference between IM and CAEBV patients. Furthermore, we observed some disease-related preferences in TRBV/TRBJ usage and combinations, as well as lots of T cell clones shared by different groups (unique or overlapped) involved in public T cell responses, which provide more detailed insights into the divergent disease evolution.

Background: The risk of infectious mononucleosis among athletes is quite debated. Some personal observations seem to suggest an increase risk of mononucleosis among athletes, because they attend always close settings with an high probability of respiratory pathogens transmission; overtraining has been also proposed as risk factor., Study Design: Cross-sectional study in a group of swimmers (aged 11-14 years) of the University Sport Centre of Bari., Methods: 40 swimmers were interviewed by healthcare personnel at the end of training courses; demographic characteristics, personal habits, information about sport training and diagnosis of mononucleosis were analysed., Results: The life-time incidence of mononucleosis was around 40%; multivariate analysis showed the association between mononucleosis and use of bottles of other persons (aOR=8.2; 95% CI=1.4-49.2; z=2.32; p=0.021) and average duration of training session was longer among subjects who reported mononucleosis than in subjects who did not indicate this disease., Conclusions: Future multi-centric studies are needed to better define the epidemiology of the mononucleosis in sport settings and to formulate appropriate recommendations to prevent the spreading of this disease.

The aim of this controlled cross-sectional study was to assess the clinical validity of elevated values of three clinically relevant transferase enzymes (aspartate transaminase [AST], alanine transaminase [ALT], and gamma-glutamyl transferase [GGT]) induced by imported infectious diseases (IDs) seen among patients consulting the Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (from 1999 to 2014) after being in the sub-/tropics. Data sets of 14,559 diseased German travelers returning from Latin America (2,715), Africa (4,574), or Asia (7,270) and of 1,536 healthy controls of German origin without recent travels were analyzed. Among the cases, the proportions of those with elevated values of AST (7.8%) and of ALT (13.4%) were significantly larger than among controls (4.0% and 10.6%, respectively), whereas for GGT, no significant difference was found (cases: 10.0%; controls: 11.4%). The study identified IDs with significantly larger proportions of both AST and ALT (hepatitis A [100%/100%], cytomegalovirus [CMV] infection [77%/81%], chronic hepatitis C [67%/67%], infectious mononucleosis [65%/77%], typhoid fever [50%/50%], cyclosporiasis [45%/66%], dengue fever [43%/35%], malaria [20%/27%], and rickettsiosis [20%/24%]), of AST alone (paratyphoid fever [42%]), of ALT alone (giardiasis [20%]), and of GGT (hepatitis A [100%], infectious mononucleosis [71%], CMV infection [58%], rickettsiosis (20%], and dengue fever [19%]). The study demonstrates that the determination of AST and ALT among travelers returning from the sub-/tropics has a high clinical validity, as their elevated values are typically caused by several imported viral, bacterial, and protozoan IDs, whereas no additional clinical validity was found by the determination of GGT., (© The American Society of Tropical Medicine and Hygiene.)

Background: The aetiology of nasopharyngeal carcinoma (NPC) remains enigmatic in endemic and non-endemic areas. Early-life infection with Epstein-Barr virus (EBV) may predispose to NPC development, whereas delayed primary infection with EBV may cause infectious mononucleosis (IM)., Methods: We used Swedish population and health registers to investigate whether potential indicators of early EBV infection, such as birth order, sibship size, maternal age and paternal age, are related to the subsequent risks for NPC and IM. We conducted two nested case-control studies, one for each health outcome, based on 251 NPC case patients, 11 314 IM case patients and five population control subjects per case matched by birth year and sex. We used conditional logistic regression modelling to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for NPC and IM., Results: The multivariate-adjusted ORs of developing NPC increased with number of siblings; the ORs associated with having one, two and three or more siblings, compared with none, were 1.59 (95% CI = 0.97, 2.62), 1.94 (95% CI = 1.17, 3.22), and 2.03 (95% CI = 1.23, 3.35), respectively (Ptrend = 0.006). This increased risk of NPC was explained mainly by having older rather than younger siblings. In contrast, lower risks of IM were observed among individuals with an increasing number of older siblings, younger siblings and total siblings., Conclusions: Early-life social environment, possibly related to EBV infection, contributes to NPC pathogenesis in non-endemic areas. This hypothesis is further supported by the clearly contrasting findings between NPC and IM., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Aim: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS)., Methods: We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls., Results: Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11-4.03), 4.31 (95% CI, 2.24-8.31), 7.96 (95% CI, 3.84-16.49), and 21.24 (95% CI, 5.48-82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9-91.4) of FCD onset. High anti-EBNA IgG was another important contributor., Conclusions: A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction., (© The Author(s), 2015.)

Background: Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education., Objective: The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size., Methods: Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors., Results: Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41-0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44-0.83). The estimates remained similar when cases with disease onset before age 28 were excluded., Conclusion: These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk., (© The Author(s), 2015.)

Introduction: Infective mononucleosis is most commonly caused by Epstein-Barr virus (EBV), and in smaller percentage by cytomegalovirus (CMV)., Objective: The aim of this paper was to determine the clinical and laboratory differences between EBV and CMV infectious mononucleosis in children., Methods: Cohort retrospective analytical research was conducted. We used data from medical history in six years period and monitored anamnestic data, frequency of inspection and palpation obtained data during physical examination, several laboratory tests, abdomen ultrasonography examination finding and emergence of disease complications. Statistical processing of data has been performed using SPSS 20., Results: Total number of examined children was 137, out of which 85.4% were with EBV and 14.6% with CMV infection. Affected children were most commonly younger than eight years. Boys were affected more often. There was no difference in frequency of high temperature, sore throat, bad breath, and respiratory symptomatology between examined children. Differences were discovered in frequency of stomachaches, eyelid swelling, skin rash and fatigue. Differences were not proven in the frequency of angina, lymphadenopathy and splenohepatomegaly between the groups. Values of transaminases and lactic dehydrogenases significantly decreased after seven days of hospitalization in both groups. In children with EBV, values of transaminases declined faster than in children with CMV. Anemia and bacterial superinfection of pharynx were most common disease complications. Thrombocytopenia was more common in children with CMV infection. Average duration of hospitalization was 6.7 days., Conclusion: In children with CMV abdominal pain, eyelid swelling, skin rash, fatigue and thrombocytopenia were more common. In children with EBV values of transaminases declined significantly faster.

Introduction: The search of HIV infected patients guided by indicator conditions (IC) is a strategy used to increase the early detection of HIV. The objective is to analyze whether a collaboration to raise awareness of the importance of early detection of HIV in 3 primary care centers influenced the proportion of HIV serology requested., Methods: Multicenter retrospective study was conducted comparing the baseline and a post-collaboration period. The collaboration consisted of training sessions and participation in the HIDES study (years 2009-2010). Patients between 18 and 64 years old with newly diagnosed herpes zoster, seborrheic eczema, mononucleosis syndrome, and leucopenia/thrombocytopenia in 3 primary care centers in 2008 (baseline period) and 2012 (post-collaboration period). The sociodemographic variables, HIV risk conditions, requests for HIV serology, and outcomes were evaluated., Results: A total of 1,219 ICs were included (558 in 2008 and 661 in 2012). In 2008 the number of HIV tests in patients with an IC was 3.9%, and rose to 11.8% in 2012 (P<.0001). The HIV infection rate was 2.2% (95% CI: 0.4-7.3) (n=2). It was estimated that 25 new cases (12 in 2008 and 13 in 2012) would have been diagnosed if they had performed the test on all patients with IC. Predictors of HIV request were, having an IC in 2012, a younger age, having an mononucleosis syndrome, and not being Spanish., Conclusions: The HIV request demand tripled, after the collaboration with primary care centers, however in 88% the test was not requested, resulting in diagnostic losses. New strategies are needed to raise awareness of the importance of early detection of HIV., (Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.)