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Epstein-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. Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated (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, and plasma cohorts, respectively. Broad 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. Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months. https://clinicaltrials.gov/, identifier NCT02335437.

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. 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. 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.

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. IM, commonly caused by the Epstein–Barr virus, has been linked with immune-mediated and inflammatory diseases. Here, the authors find evidence of an association between severe IM and IBD in nationwide registry data from Denmark.

Epstein–Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases 1 , 2 . The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder 3 . Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV 4 . Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit 5 , 6 . In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation 7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8 + T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA–IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA–IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells. IL-27RA–IL-27 has a critical role in the immunity to EBV, and this defence is hijacked by Epstein–Barr virus to promote the expansion of infected transformed B cells

A 16-year-old, previously healthy girl presents with a several-day history of fever, sore throat, and malaise. She appears very tired and has a temperature of 39°C. A physical examination is remarkable for diffuse pharyngeal erythema with moderately enlarged tonsils and the presence of several enlarged, tender anterior and posterior cervical lymph nodes. How should this case be managed? A 16-year-old, previously healthy girl presents with a several-day history of fever, sore throat, and malaise. A physical examination is remarkable for diffuse pharyngeal erythema with moderately enlarged tonsils and the presence of several enlarged lymph nodes. How should this case be managed? Listen to the full text of this article. Foreword This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. Stage A 16-year-old, previously healthy girl presents with a several-day history of fever, sore throat, and malaise. She appears very tired and has a temperature of 39°C. A physical examination is remarkable for diffuse pharyngeal erythema with moderately enlarged tonsils and the presence of several enlarged, tender anterior and posterior cervical lymph nodes. How should this case be managed? The Clinical Problem Infectious mononucleosis is a clinical syndrome that is most commonly associated with primary Epstein–Barr virus (EBV) infection. EBV is a gamma herpesvirus with a double-stranded DNA genome of about 172 kb. 1 Natural EBV infection occurs in humans only . . .

Multiple sclerosis (MS) appears to develop in genetically susceptible individuals as a result of environmental exposures. Epstein-Barr virus (EBV) infection is an almost universal finding among individuals with MS. Symptomatic EBV infection as manifested by infectious mononucleosis (IM) has been shown in a previous meta-analysis to be associated with the risk of MS, however a number of much larger studies have since been published. We performed a Medline search to identify articles published since the original meta-analysis investigating MS risk following IM. A total of 18 articles were included in this study, including 19390 MS patients and 16007 controls. We calculated the relative risk of MS following IM using a generic inverse variance with random effects model. This showed that the risk of MS was strongly associated with IM (relative risk (RR) 2.17; 95% confidence interval 1.97-2.39; p<10(-54)). Our results establish firmly that a history of infectious mononucleosis significantly increases the risk of multiple sclerosis. Future work should focus on the mechanism of this association and interaction with other risk factors.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a severe hyperinflammatory disorder induced by overactivation of macrophages and T cells. This study aims to identify the risk factors for the progression from infectious mononucleosis (EBV-IM) to EBV-HLH, by analyzing the laboratory parameters of patients with EBV-IM and EBV-HLH and constructing a clinical prediction model. The outcome of this study carries important clinical value for early diagnosis and treatment of EBV-HLH. A retrospective analysis was conducted on 60 patients diagnosed with EBV-HLH and 221 patients diagnosed with EBV-IM at our hospital between November 2018 and January 2024. Participants were randomly assigned to derivation and internal validation cohorts in a 7:3 ratio. LASSO regression and logistic regression analyses were employed to identify risk factors and construct the nomogram. Ferritin (OR, 213.139; 95% CI, 8.604-5279.703; P=0.001), CD3 CD16 CD56 % (OR, 0.011; 95% CI, 0-0.467; P=0.011), anti-EBV-NA-IgG (OR, 57.370; 95%CI, 2.976-1106.049; P=0.007), IL-6 (OR, 71.505; 95%CI, 2.118-2414.288; P=0.017), IL-10 (OR, 213.139; 95% CI, 8.604-5279.703; P=0.001) were identified as independent predictors of EBV-HLH. The prediction model demonstrated excellent discriminatory capability evidenced by an AUC of 0.997 (95% CI,0.993-1.000). When visualized using a nomogram, the ROC curves for the derivation and validation cohorts exhibited AUCs of 0.997 and 0.993, respectively. These results suggested that the model was highly stable and accurate. Furthermore, calibration curves and clinical decision curves indicated that the model possessed good calibration and offered significant clinical benefits. The nomogram, which was based on these five predictors, exhibited robust predictive value and stability, thereby can be used to aid clinicians in the early detection of EBV-HLH.

BackgroundBenign multiple sclerosis (MS), characterised by minimal disability despite long disease duration, remains poorly understood in terms of its determinants and prognostic implications. While lifestyle factors have been implicated in modifying disease progression, their role in distinguishing benign and non-benign MS remains unclear.MethodsWe conducted a comparative analysis of patients with benign (n=2040) and non-benign MS (n=4283) using data from Swedish nationwide case-control studies with long-term follow-up. Logistic regression models were used to analyse associations between a history of infectious mononucleosis (IM) and lifestyle factors (smoking, body mass index, fish consumption and sun exposure habits) and the likelihood of benign MS. Additionally, Cox regression was used to follow patients with benign MS from the 15-year mark onward, identifying factors associated with the transition to non-benign MS over time.ResultsThe odds of having benign MS were reduced in association with a history of IM (OR 0.54, 95% CI 0.45 to 0.65), adolescent overweight and obesity (OR 0.69, 95% CI 0.56 to 0.85 and 0.46, 95% CI 0.32 to 0.66, respectively) and infrequent fish consumption (OR 0.72, 95% CI 0.60 to 0.88). Similar associations were observed for the risk of transitioning from benign to non-benign MS over time.ConclusionsA history of IM and modifiable lifestyle factors significantly influence the probability of a benign disease course in MS. These findings underscore the potential for targeted lifestyle interventions to improve MS outcomes. Further research is needed to elucidate the mechanisms by which a past IM infection can continue to influence MS progression long after the initial infection.

Introduction: The objectives of this study were to identify clinical and laboratory markers of infectious mononucleosis (IM) in children, investigate the risk factors for liver damage and prolonged hospitalization, and enhance Epstein-Barr virus (EBV) diagnostic precision. Methodology: This retrospective study analyzed 288 pediatric IM cases hospitalized from January 2023 to December 2024. Clinical features, laboratory parameters, and EBV-DNA loads were evaluated using statistical analyses to identify predictors of disease severity and outcomes. Results: Among the 288 children (median age: 5 years; 48.3% male), fever, cervical lymphadenopathy, creatine kinase (CK), IgM, and CD4/CD8 ratios were significantly associated with high EBV-DNA load. Liver damage (35.1% of cases) correlated with age, splenomegaly, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), ferritin, and immune markers (p < 0.05). Prolonged hospitalization was associated with hepatomegaly, ALT, AST, GGT, LDH, and ferritin levels (p < 0.05). Multivariate analysis identified fever as a predictor of high EBV-DNA load; while age, LDH, and ferritin were independent risk factors for liver damage. Hepatomegaly was a key predictor of extended hospitalization (p < 0.05). Conclusions: IM predominantly affected children aged 3–7 years in Hangzhou. Fever predicted high EBV-DNA load, while elevated LDH, ferritin, and hepatomegaly signaled increased risks of liver damage and prolonged hospitalization, informing more precise management strategies.

Epstein-Barr is a ubiquitous virus that infects 95% of the world population at some point in life. Although Epstein-Barr virus (EBV) infections are often asymptomatic, some patients present with the clinical syndrome of infectious mononucleosis (IM). The syndrome most commonly occurs between 15 and 24 years of age. It should be suspected in patients presenting with sore throat, fever, tonsillar enlargement, fatigue, lymphadenopathy, pharyngeal inflammation, and palatal petechiae. A heterophile antibody test is the best initial test for diagnosis of EBV infection, with 71% to 90% accuracy for diagnosing IM. However, the test has a 25% false-negative rate in the first week of illness. IM is unlikely if the lymphocyte count is less than 4,000 mm . The presence of EBV-specific immunoglobulin M antibodies confirms infection, but the test is more costly and results take longer than the heterophile antibody test. Symptomatic relief is the mainstay of treatment. Glucocorticoids and antivirals do not reduce the length or severity of illness. Splenic rupture is an uncommon complication of IM. Because physical activity within the first three weeks of illness may increase the risk of splenic rupture, athletic participation is not recommended during this time. Children are at the highest risk of airway obstruction, which is the most common cause of hospitalization from IM. Patients with immunosuppression are more likely to have fulminant EBV infection.