Mononucleosis Research Articles

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

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. 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. 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.

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

Epstein-Barr virus (EBV) is thought to be a necessary causative agent in the development of multiple sclerosis (MS). Infectious mononucleosis (IM), which occurs up to 70% of adolescents and young adults with primary EBV infection, appears to be a further risk factor but few studies have been highly powered enough to explore this association by time since IM diagnosis. The objective was to quantify the risk of MS in individuals with IM compared with the general population, with particular focus on time since IM diagnosis. In this retrospective cohort study using English national Hospital Episode Statistics from 2003 to 2023, patients with a hospital diagnosis of IM were compared with the general population for MS incidence. MS incidence in patients with IM was nearly three times higher than the general population after multivariable adjustment (adjusted hazard ratio = 2.8, 95% confidence interval (CI = 2.3-3.4), driven by strong associations at long time intervals (>5 years) between IM diagnosis and subsequent MS diagnosis. While EBV infection may be a prerequisite for MS, the disease process of IM (i.e. the body's defective immune response to primary EBV infection) seems to be, in addition, implicated over the long term.

Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infectedtransformed B cells.

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

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

Epstein - Barr Virus Salivary Shedding in Patients with Acute Infectious Diseases: A Pilot Study.

Epstein-Barr virus (EBV) is a widely disseminated herpesvirus for which antibodies have been demonstrated in over 90% of adults worldwide. After subclinical primary EBV infections, as well as after infectious mononucleosis, the virus can be shed in saliva for a prolonged period of time. Diseases and disorders that can induce EBV salivary shedding include mental disorders and sex, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, malaria and HIV infection. Since the occurrence of EBV in saliva during acute infectious diseases has not yet been systematically researched, we aimed to investigate the possible relationship between acute infectious diseases and salivary shedding of EBV. This pilot cross-sectional study included consenting adults hospitalized for acute infectious conditions and their peers free of acute infectious diseases. A total of 40 patients with acute infectious diseases were enrolled, along with 41 adults free of acute infections. Peripheral venous blood samples for serodiagnosis and saliva samples for EBV PCR testing were collected from both groups. We fitted logit and general linear models to proportions and to ln (viral copy counts) to generate adjusted proportions and geometric mean values in the two groups of subjects. We used SAS for Windows 9.4. The most common acute infectious disease was COVID-19 pneumonia, followed by hemorrhagic fever with renal syndrome. Crude proportions of people with positive serological test results and those with saliva viral shedding were similar in the two groups. The presented preliminary data do not indicate acute infectious conditions as a marked "contributor" in increasing salivary EBV shedding.

Clinical analysis of infectious mononucleosis complicated with acute acalculous cholecystitis.

This study aimed to investigate specific clinical diagnostic methods for children with infectious mononucleosis (IM) complicated by acute acalculous cholecystitis (AAC). We conducted a retrospective analysis of 171 cases of IM diagnosed in the infectious disease ward of Children's Hospital of Nanjing Medical University between January 2020 and December 2020. All IM patients underwent abdominal ultrasound examinations to assess the liver, gallbladder, and spleen. Fourteen patients with symptoms of AAC underwent a follow-up assessment one week later. The estimated incidence of AAC in hospitalized IM children was 8.2%. Both groups of patients presented with fever, abdominal pain, and eyelid edema upon admission. Characteristic radiological findings of AAC were observed, including gallbladder (GB) distention, increased GB wall thickness and increased common bile duct diameter. Analysis of laboratory results revealed no statistically significant differences in leukocyte, absolute lymphocyte count, CD3+, CD3 + CD4+, CD3+ CD8+, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), or Gamma-Glutamyl Transferase (GGT) levels between the AAC(+) and AAC(-) groups on admission. However, these parameters were not significant risk factors for AAC. After discharge, relevant indicators in non-AAC patients gradually decreased to normal levels, while those in AAC(+) patients did not show a significant decrease. While cases of IM complicated by AAC are relatively uncommon, the utilization of abdominal ultrasound offers a reliable tool for confirming this diagnosis. Routine abdominal ultrasound examinations are recommended for IM patients to improve early detection and treatment of associated conditions.

Epstein-Barr virus gp42 antibodies reveal sites of vulnerability for receptor binding and fusion to B cells

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with B cell lymphomas. EBV glycoprotein 42 (gp42) binds HLA class II and activates membrane fusion with B cells. We isolated gp42-specific monoclonal antibodies (mAbs), A10 and 4C12, which use distinct mechanisms to neutralize virus infection.mAb A10 was more potent than the only known neutralizing gp42 mAb, F-2-1, in neutralizing EBV infection and blocking binding to HLA class II. mAb 4C12 was similar to mAb A10 in inhibiting glycoprotein-mediated B cell fusion but did not block receptor binding, and it was less effective in neutralizing infection. Crystallographic structures of gH/gL/gp42/A10 and gp42/4C12 complexes revealed two distinct sites of vulnerability on gp42 for receptor binding and B cell fusion. Passive transfer of mAb A10 into humanized mice conferred nearly 100% protection from viremia and EBV lymphomas after EBV challenge. These findings identify vulnerable sites on EBV that may facilitate therapeutics and vaccines.

The Economic Burden of Epstein–Barr Virus Infection in the Russian Federation

Introduction: Epstein–Barr virus-related diseases are of great medical and social importance, which requires assessment of economic losses due to costs of medical care and sickness absenteeism. Objective: To propose a methodology for assessing economic damage and to use it for quantification of total damages caused by Epstein–Barr virus (EBV) infections in the Russian Federation in 2022. Materials and methods: The economic damage from EBV infections was determined using official statistics on cases of infectious mononucleosis (2022), upper respiratory tract infections, cardiac arrhythmias, atopic dermatitis, dorsopathy, chronic tonsillitis in the acute phase, cerebrovascular disease, psoriasis, and multisystem inflammatory syndrome associated with COVID-19. Results: Based on the methodology for assessing economic damages described in the article, we found that the total financial losses from EBV-associated diseases in the Russian Federation in 2022 amounted to 1,203.0 billion or 1.2 trillion rubles, which is significantly higher than similar values for all other registered infectious diseases with the exception of COVID-19. COVID-19-related multisystem inflammatory syndrome, upper respiratory tract infections, and cerebrovascular disease account for more than 90 % of all losses. The structure of total costs is dominated by indirect economic losses (1,096.75 billion rubles or 91.2 %) due to sickness absence from work. Conclusion: The findings allow us to outline directions of developing measures to reduce the economic damage from EBV-associated diseases.

Çocukluk çağı Kronik ve Persistan Lenfadenopatilerin Ultrason ve Laboratuvar Veriler eşliğinde Öngörülebilirliği; Bir Çocuk Hematoloji-Onkoloji Polikliniği Deneyimi

Aim:
 Lymphadenopathies occupy an important part of pediatric hematology-oncology practice. More than 95 per cent of cases are known to be reactive, and infection-related. Lymphadenopathies are followed up at 1-3-6 month intervals, and the process requires ultrasound follow-up. Our study aimed to compare the persistent and non-persistent cases.
 Results: In our study, lymphadenopathy cases (n=93) admitted to our pediatric haematology-oncology outpatient clinic between 2022-2023 were examined and diagnosed; reactive lymph nodes (n=76)(81. 7%), infectious mononucleosis (n=9)(9. 7%), tuberculosis (n=1)(1%), lymphoma (n=2)(2%), benign cytology (n=2)(2%). Mean age ± standard deviation (SD); 8. 2±4. 4, number of girls; 42 (45. 2%). The median time to resolution of acute (n=8)(8. 6%), subacute (n=26)(28%), chronic (n=59)(63. 4%) lymphadenopathy was 1 [5-155] week. Cases with and without ultrasonographic disappearance of lymphadenopathy were compared; the mean hemoglobin value (g/dL) (12. 7±1. 4 vs. 12. 3±1. 2, respectively) (p=0. 047) and platelet value (x10³/mm³) (334. 2±108. 012 vs. 288. 4±89. 5, respectively) (p=0. 047) were higher and the presence of hilar vascularity on ultrasonography (76% vs. 98. 1%) (p=0. 001) was LOWER in those who disappeared compared to those who did not disappear. There was no correlation between hypoechoic lymph node, indistinct border, necrosis, fatty hilus, perinodal cortical vascularity, cortical thickening, presence of lymph node in more than one region and non-loss of lymph node.
 Conclusion: In conclusion, it has been shown that in the presence of lymphadenopathy, elevated hemoglobin and platelets, together with the presence of hilar vascularity, may be predictive findings in the failure of the lymph node to disappear.
 Key words: lymphadenopathy, ultrasonography, haemoglobin, platelets, childhood

Novel plasma microRNA expression features in diagnostic use for Epstein-Barr virus-associated febrile diseases

BackgroundEpstein-Barr virus (EBV) is widely infected in humans and causes various diseases. Among them, microRNAs of EBV play a key role in the progression of EBV-associated febrile diseases. There're few specific indicators for rapid differential diagnosis of various febrile diseases associated with EBV, and the lack of more reliable screening methods with high diagnostic utility has led to spaces for improvement in the accurate diagnosis and efficient treatment of relevant patients, making EBV infection a complicated clinical problem. With recent advances in plasma microRNA testing, the apparent presence of EBV microRNAs in plasma can help screen for EBV infection. The gene networks targeted by these microRNAs can also indicate potential biomarkers of EBV-associated febrile diseases. This study aimed to identify some novel miRNAs as potential biomarkers for early diagnosis of respectively EBV-associated febrile diseases. Materials and methodsA total of 110 participants were recruited for this task. First, we performed high-throughput sequencing and preliminary PCR validation of differentially expressed miRNAs in 15 participants with EBV-associated fever (divided into 5 groups, common EBV carriers, infectious mononucleosis (IM) and chronic active EBV infection (CAEBV), EBV-associated Hemophagocytic Lymphohistiocytosis (EBV-HLH), and 3 healthy individuals). After a comprehensive analysis, 10 miRNAs with abnormal expression were screened, and then qRT-PCR was performed in the rest of 95 participants to detect the validation of miRNAs expression in plasma samples. Thereafter, we further investigated their potential for clinical application in EBV-related febrile diseases by using a combination of Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and Protein-protein interaction network analysis. ResultsThrough identification and detailed analysis of the obtained data, we found significant differences in the expression of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p in blood samples from patients with different EBV-related febrile diseases. We found that the expression levels of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p in plasma are indicative of determining different disease types of EBV-related febrile diseases, while EBV-miR-BART22 and EBV-miR-BART2-3p may be potential therapeutic targets. ConclusionThe expression levels of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p suggest that they may be used as transcriptional features for early differential diagnosis of EBV-related febrile diseases, and EBV-miR-BART22 and EBV-miR-BART2-3p may be potential therapeutic targets.

Role of flowcytometry in atypical lymphocytosis

Infectious mononucleosis (IM) is a benign condition defined by lymphomononuclear cell proliferation. Symptoms range from a vague constitutional syndrome to fever, rash, jaundice, hepatosplenomegaly, lymphadenopathy, and in rare cases, autoimmune hemolytic anemia. The viruses responsible for this syndrome are EBV (the most prevalent), CMV, HIV, Hepatitis virus, Adenovirus, and others. Because the virus mostly impacts lymphomononuclear cells and the reticuloendothelial system, it may trigger intense lymphoproliferation, leading to uncommon manifestations in peripheral smear. These can be misdiagnoses as leukemia/lymphoma. The clinical profile of a brief history, mild organomegaly, and peripheral smear morphology commonly overlaps. This pitfall in the diagnosis can lead to ineffective treatment. Immunophenotyping by flowcytometry or immunohistochemistry, a mono-spot test, and specific viral ag/ab assays are required for a correct diagnosis. Flowcytometry profiles are not always adequate to rule out neoplastic proliferations. We provide a case study of a young teenage boy who arrived with an abrupt history of low-grade fever, hepatosplenomegaly, cervical lymphadenopathy, elevated leukocyte count, and atypical lymphoid cells on peripheral smear. What was previously thought to be a hematological malignancy was discovered to be a self-limiting acute IM (CMV caused), and the patient was discharged after a brief course of treatment.

Epstein-Barr virus (EBV) DNAemia in saliva of viral encephalitis and nasopharyngeal carcinoma patients.

Epstein-Barr virus (EBV) is a lymphotropic virus that causes diseases ranging from a flu-like illness called infectious mononucleosis to nasopharyngeal carcinoma, Burkitt's lymphoma, and central nervous system (CNS) infection. Detection of EBV DNA is usually done using whole blood samples taken from the patients. We undertook the detection of EBV in blood, cerebrospinal fluid (CSF), and saliva by real-time quantitative PCR in two patients, one with a history of nasopharyngeal carcinoma, and the other having a case of viral encephalitis. EBV was detected only in saliva, whole blood in both patients, and CSF in the second case tested negative. This case series illustrates the importance of testing for EBV DNAemia in saliva by real-time polymerase chain reaction (PCR) to rule in a diagnosis of EBV.

Epstein-Barr virus: the mastermind of immune chaos.

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

Comparison of Eosinophil Counts in Inflammatory Conditions: Multisystem Inflammatory Syndrome in Children, Kawasaki Disease, and Infectious Mononucleosis.

This study examined the distinctions between multisystem inflammatory syndrome associated with coronavirus disease 2019, Kawasaki disease, and infectious mononucleosis. These three inflammatory disorders have commonalities according to clinical and laboratory results, particularly in relation to eosinophil levels. In this retrospective, single-center study, we documented the examination records (acute phase reactants and complete blood count) and clinical and cardiological findings of 130 patients diagnosed with multisystem inflammatory syndrome, Kawasaki disease, and infectious mononucleosis. These patients were treated and received follow-up care in our hospital from March 12, 2020, to September 13, 2022, as per the hospital records. Statistical analyses were performed using NCSS 2007, version 1 software. Eosinopenia was more prevalent in children with multisystem inflammatory syndrome than in those with Kawasaki disease, who showed normal or elevated eosinophil counts. The eosinophil counts in patients with infectious mononucleosis typically fell within the normal range. Our study found no correlation between the eosinophil counts and cardiac involvement in pediatric patients with either condition. These findings indicate a higher prevalence of eosinopenia in patients with multisystem inflammatory syndrome, irrespective of cardiac involvement, than in those with Kawasaki disease. Despite similarities in clinical findings, Kawasaki disease and multisystem inflammatory syndrome in children necessitate further studies for distinct characteristic elucidation.

A guide to glandular fever

Amy Noakes looks at the symptoms and treatment of infectious mononucleosis, also known as glandular fever

Comparison of plasma proteomic profiles of patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and infectious mononucleosis.

Primary Epstein-Barr virus (EBV) infection occasionally causes EBV-infectious mononucleosis (EBV-IM) and EBV-hemophagocytic lymphohistiocytosis (EBV-HLH). Although EBV-IM is mostly mild and self-limiting, EBV-HLH is a life-threatening disease characterized by excessive immune activation. However, the pathogenesis of EBV-HLH is yet to be fully elucidated. A diagnostic biomarker for EBV-HLH is desirable because early diagnosis and treatment are critical for the effective management of patients. In this study, the proteomic profiling of plasma was performed using liquid chromatography-mass spectrometry to identify proteins specific to EBV-IM and EBV-HLH. Furthermore, pathway analysis was performed for the proteins upregulated in patients with EBV-IM and EBV-HLH. Compared to healthy controls, 63 and 18 proteins were upregulated in patients with EBV-IM and EBV-HLH, respectively. Pathway and process enrichment analyses revealed that the complement system was the most enriched category of upregulated proteins in EBV-IM, whereas proteins related to immune effector processes were the most enriched in EBV-HLH. Among the 18 proteins upregulated in EBV-HLH, seven were exclusive to EBV-HLH. These specific proteins were associated with three pathways, and apolipoprotein E was commonly found in all the pathways. Proteomic analysis may provide new insights into the host response to EBV infection and the pathogenesis of EBV-related diseases.

P1121 The risk of inflammatory bowel disease following serious infectious mononucleosis: A Danish nested case-control study

Abstract Background Epstein-Barr virus (EBV) infects ~95% of adults globally and limited early life transmission opportunities can delay EBV exposure till adolescence/early adulthood, increasing the risk of severe EBV infection, which most commonly manifests as infectious mononucleosis (IM). This study sought to investigate a potential aetiological association between IM and inflammatory bowel disease (IBD). Methods In this longitudinal nested case-control study, Danish nationwide registries were used to identify 37,156 IBD patients and 222,936 sex- and age-matched healthy controls, between 2005-2021. Logistic regression was used to calculate the odds ratio (OR) for IM hospitalisation prior to IBD diagnosis stratified by sex, age at IM diagnosis, age at IBD diagnosis, and IBD subtype (Crohn’s disease [CD] or ulcerative colitis [UC]). Additionally, exposure-controlled time-to-event analyses were used to explore the association between IM hospitalization and poor IBD prognosis. This association was measured using the occurrence of IBD-related hospitalization, surgery, complication and/or anti-TNF therapy commencement up to 10 years post-IBD diagnosis. Results Previous IM hospitalisation was significantly associated with the development of both CD (OR: 1.44, 95% CI: 1.20-1.73) and UC (OR: 1.27, 95% CI: 1.09-1.47). Sex was not found to be a significant effect modifier of this association for either CD (p=0.4) or UC (p=0.9). Those hospitalised with IM at a younger age had a higher odd of developing CD than those hospitalised in early adulthood (0-14-years OR: 2.60 [95% CI: 1.41-4.59]; >20-years OR: 2.04 [95% CI: 1.23-3.25]). A similar pattern was observed for UC development (0-14-years OR: 2.62 [95% CI: 1.44-4.55]; >20-years OR: 1.50 [95% CI: 0.97-2.25]). Poor disease prognosis following hospitalisation with IM within 10 years post-IBD diagnosis was only seen in CD (CD IRR: 1.52 [95% CI: 1.20-1.92]; UC IRR: 0.87 [95% CI: 0.65-1.16]). Conclusion This study demonstrated an association between IBD development and prior hospitalisation with IM, indicating the possibility of EBV infection as a significant contributor to IBD development. Strengthening understanding of IBD development can contribute to the prevention of IBD and improve management.

P1167 Inflammatory Bowel Disease: a phenome-wide pre- and post-diagnostic association study

Abstract Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is known to be associated with various extra-intestinal manifestations, impacting organ systems beyond the gastrointestinal tract. Identifying comorbidities in IBD and the timing of their development can provide valuable insight into the mechanisms underlying IBD development. Methods We conducted the first population- and disease-wide phenomic association study in IBD, using >6 million ICD-10 coded healthcare contacts from 10 years before and up to 17 years after IBD diagnosis to investigate associations with 1583 diseases. To explore co-morbidities with potential aetiological significance with IBD, we additionally assessed the strength of association with all diseases in the pre-diagnostic compared with the post-diagnostic period. To correct for multiple testing, we adjust our significance threshold (p<0.05) with the Bonferroni correction, resulting in an adjusted p-value of 7.90×10, which we refer to as disease-wide statistical significance. Results We identified 312 disease-wide statistically significant associations with 125 of these diseases appearing up to 10 years before diagnosis. The risk of immune-mediated diseases and extra-intestinal manifestations are among those diseases increased up to 10 years prior to IBD diagnosis (psoriasis: CD-RR: 2.57, 95% CI: 2.00-3.29; UC-RR: 1.54, 95% CI: 1.25-1.87; enteropathic arthropathies: CD-RR: 3.57, 95% CI: 2.65-4.78; UC-RR: 1.8, 95% CI: 1.38-2.32). This was also the case for gastroenterological and liver disorders (gall stones: CD-RR: 1.82, 95% CI: 1.62-2.04; UC-RR: 1.26, 95% CI: 1.15-1.37; acute pancreatitis: CD-RR: 1.83, 95% CI: 1.30- 2.53; UC-RR: 2.27, 95% CI: 1.84-2.79). The risk of cardiometabolic diseases and neuropsychological disorders had increased disease-wide statistical significance both pre- and post-diagnostically, whereas potential sequelae of treatment, such as osteoporosis (CD-HR: 2.56, 95% CI: 2.30-2.86; UC-HR: 1.92, 95% CI: 1.79-2.07) or herpes simplex infections (CD-HR: 4.04, 95% CI: 2.76-5.91; UC-HR: 1.69, 95% CI: 1.2-2.38) were primarily seen post-diagnostically. Of potential aetiological importance to CD, diagnosis with infectious mononucleosis (RR: 1.87, 95% CI: 1.37-2.52) was significantly associated with the pre- compared to the post-diagnostic period. Conclusion Our results demonstrate IBD as an essentially multisystemic disease, particularly manifesting as gastrointestinal, metabolic, immune, and neuropsychological disorders, present up to 10 years prior to IBD diagnosis. Infectious diseases of aetiological interest identified warrant further investigation.

Joint Flexibility and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After Mononucleosis

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

One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus.

Infectious mononucleosis after primary infection with Epstein-Barr virus (EBV-IM) has been linked to the development of myalgic encephalomyelitis/chronic fatigue-syndrome (ME/CFS) in children, adolescents, and young adults. Here, we present clinical phenotypes and follow-up data from a first German cohort of young people with ME/CFS following EBV-IM. 12 adolescents and 13 young adults were diagnosed with IM-triggered ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise (PEM) and a history of confirmed EBV primary infection as triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed and re-evaluated 6 and 12 months later. Young adults displayed more severe symptoms as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS while all young adults continued to fulfill the Canadian consensus criteria. Improvement in adolescents was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1-34.9) months. ME/CFS following EBV-IM is a severely debilitating disease often diagnosed late and with limited responses to conventional medical care, especially in adults. Although adolescents may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed to improve medical care and pave the way to recovery.