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

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

Infectious Mononucleosis: An Updated Review.

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

Infectious Mononucleosis: Rapid Evidence Review.

Infectious mononucleosis is a viral syndrome characterized by fever, pharyngitis, and posterior cervical lymphadenopathy. It is usually caused by Epstein-Barr virus and most often affects adolescents and young adults 15 to 24 years of age. Primary transmission is through close personal contact with a person who is infected, particularly their saliva. Cost-effective, efficient initial laboratory testing for acute infectious mononucleosis includes complete blood count with differential (to assess for greater than 40% lymphocytes and greater than 10% atypical lymphocytes) and a rapid heterophile antibody test. The heterophile antibody test has a sensitivity of 87% and specificity of 91% but can have a false-negative result in children younger than five years and in adults during the first week of illness. The presence of elevated liver enzymes increases clinical suspicion for infectious mononucleosis in the setting of a negative heterophile antibody test result. Epstein-Barr viral capsid antigen-antibody testing is more sensitive and specific but more expensive and takes longer to process than the rapid heterophile antibody test. Treatment of infectious mononucleosis is supportive; routine use of antivirals and corticosteroids is not recommended. Current guidelines recommend that patients with infectious mononucleosis not participate in athletic activity for three weeks from onset of symptoms. Shared decision-making should be used to determine the timing of return to activity. Immunosuppressed populations are at higher risk of severe disease and significant morbidity. Epstein-Barr virus infection has been linked to nine types of cancer, including Hodgkin lymphoma, non-Hodgkin lymphoma, and nasopharyngeal carcinoma, and some autoimmune diseases.

Complicaciones ORL severas por mononucleosis infecciosa en adolescentes sanos: 2 casos clínicos y revisión de la literatura / ENT severe complications of infectious mononucleosis in healthy adolescents: report of two cases and literature review

Resumen La mononucleosis infecciosa (MI) es un cuadro clínico generalmente benigno y autolimitado en la infancia y adolescencia debido a la primoinfección del virus de Epstein-Barr caracterizado por la triada de faringitis, fiebre y adenopatías. El riesgo de complicaciones aumenta con la edad y la inmunosupresión, siendo las complicaciones letales más frecuentes las asociadas a rotura esplénica, alteraciones neurológicas y obstrucción de la vía aérea por el aumento del tamaño amigdalar. Los abscesos cervicales asociados a MI son poco frecuentes, siendo mayoritariamente periamigdalinos e intraamigdalares. Presentamos dos casos quirúrgicos de abscesos cervicales profundos de gran tamaño con afectación retrofaríngea y parafaríngea en adolescentes sanos de corta edad (14 y 15 años), sin ningún tipo de inmunosupresión o factores de riesgo, uno de ellos asociado además, a una relevante hemorragia amigdalar espontanea, condición no descrita previamente en la literatura en relación a MI en un paciente tan joven.

Abstract Infectious mononucleosis (MI) is a generally benign and self-limited condition in childhood and adolescence due to the primary EBV infection characterized by the triad of pharyngitis, fever, and lymphadenopathies. The risk of complications increases with age and immunosuppression. The most frequent fatal complications are those associated with splenic rupture, neurological alterations, and airway obstruction due to increased tonsillar size. Cervical abscesses associated with MI are rare, being mostly peritonsillar and intra-tonsil. We present two surgical cases of big deep cervical abscesses with retropharyngeal and parapharyngeal involvement in healthy very young adolescents (14 and 15 years old), without any type of immunosuppression or risk factors, one of them associated with a clinically relevant spontaneous tonsillar bleeding, which had not been described in the literature associated with MI in such young patient.

[Infectious mononucleosis in practice of otorhinolaryngologist]. / Infektsionnyi mononukleoz v praktike vracha-otorinolaringologa.

Infectious mononucleosis (IM) is an acute viral infection that usually occurs with fever, acute tonsillitis, affects lymph nodes, liver, spleen, and with specific changes in the hemogram. One of the most frequent symptoms of the disease is sore throat which leads people to otorhinolaryngologist. Several pathogens may be the cause of IM, but Epstein-Barr virus(EBV) plays a key role. EBV is a γ-herpes virus and about 90% of world`s population is infected with this one. Severe IM can lead to potential life-threating conditions, for example upper airway obstruction, spleen rupture. In addition to acute IM, EBV-infection can lead to a number of neoplastic and autoimmune diseases. Due to the non-specificity of IM symptoms and the emerging difficulties in laboratory and serological diagnosis of this disease, the problem of timely diagnosis and treatment in this category of patients remains very relevant.

Infectious Mononucleosis: diagnosis and clinical interpretation.

EBV is the sole causative agent of the acute illness in humans described either as infectious mononucleosis (IM), or glandular fever. IM, when not clinically silent, can present in patients with at least two of the classic triad of symptoms of fever, pharyngitis, and lymphadenopathy. Challenges for the clinician arise when atypical cases present. Early, accurate and informed laboratory test results are vital for diagnosis, appropriate treatment, and management. A key challenge for the practitioner, particularly in cases where the illness can present atypically, is distinguishing bacterial tonsillitis infections from early acute IM. The ability to draw on timely, clear, and insightful laboratory results to distinguish viral from bacterial infection is vital. Correct and prompt diagnosis of IM can help prevent the unnecessary administration of antibiotics and mitigate the need for other expensive exploratory tests in cases of IM that present with splenomegaly, lymphadenopathy, or suspect haematological conditions. Good communication between the requesting clinician and those carrying out the investigative process, and between the different laboratory departments involved, is good practice and would ultimately benefit the patient. This communication will comprehensively review the aetiology, clinical presentation, and laboratory findings in IM with a view to promoting further research and so derive a standard diagnostic algorithm of the condition.

Kawasaki disease with a concomitant primary Epstein - Barr virus infection.

BACKGROUND: Kwasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries. The cause of KD remains unknown. The presumed theory is that KD occurs due to one or more infectious agents who evoke an abnormal immunological response in susceptible individuals. Epstein - Barr virus (EBV) infection has been considered as a suspected causative agent because of the potential effect on the immune system. CASE PRESENTATION: A previously healthy 19 month old boy presented with a 6 day history of fever accompanied by a diffuse macular erythematous rash that appeared 1 day after. The physical examination on admission revealed bilateral non-suppurative conjunctivitis, dry fissured and injected lips without "strawberry" tongue, diffuse macular rash on the trunk, face and limbs, swelling of the hands and feet, and right cervical lymphadenopathy (2 cm in diameter). Following fulfillment of all the clinical criteria, the diagnosis of KD was made and treatment with IVIG 2 g/Kg was administered along with oral aspirin (80 mg/ kg/day). However, despite the treatment, he remained febrile for an additional 2 days with persistent clinical manifestations. Therefore, he received a second 2 g/kg IVIG course with a favorable response. On the 14th day of illness the patient became febrile again and was readmitted. Blood examinations revealed remarkable leukocytosis up to 35.7 X 109/L with 87.3% lymphocytes and the blood smear revealed atypical lymphocytes and monocytes. The liver enzymes were elevated. The serology for infectious mononucleosis from his first admission revealed: IgM CMV (+), IgG CMV (-); IgM VCA EBV (+) IgG VCA EBV (-), IgG EBNA (-). To confirm infectious mononucleosis following the administration of 2 doses of IVIG, serum EBV PCR was performed and was positive (1.6X 103 cp/ml). CONCLUSIONS: We describe here a case of KD with a concomitant primary EBV infection. To the best of our knowledge, this is the first case in western country that describes KD with acute EBV infection as confirmed by PCR. The case we described stands as a contribution in favor of the possible role of EBV in the development of KD.

Spontaneous splenic rupture in a patient with infectious mononucleosis.

We present a case of spontaneous, atraumatic splenic rupture secondary to Epstein-Barr virus (EBV) infection, in a young, female patient. Splenic rupture is a rare complication of EBV infection, but is associated with the highest mortality. Additionally, this case illustrates the diagnostic challenge in a patient presenting in atypical manner, with only left-sided pleuritic chest pain, and lacking any of the classical tonsillitis symptoms associated with EBV infection.

Infectious Mononucleosis Management in Athletes.

Infectious mononucleosis is a common condition occurring in athletic training rooms. Most cases are due to Epstein-Barr virus infections (upward of 90%). Although treatment generally consists of symptomatic care, there is clinical variation in laboratory workup leading to diagnosis and in the method of return to play decision making. The authors suggest a systematic approach to laboratory evaluation and return to play decisions to minimize clinical variation. The most feared complication of infectious mononucleosis is potential splenic rupture. There have been several examples of the successful use of serial ultrasonography to help make maximally informed return to play decisions.

Epstein-Barr virus and its association with disease - a review of relevance to general practice.

BACKGROUND: General practitioners encounter the vast majority of patients with Epstein-Barr virus-related disease, i.e. infectious mononucleosis in children and adolescents. With the expanding knowledge regarding the multifaceted role of Epstein-Barr virus in both benign and malignant disease we chose to focus this review on Epstein-Barr virus-related conditions with relevance to the general practitioners. A PubMed and Google Scholar literature search was performed using PubMed's MeSH terms of relevance to Epstein-Barr virus/infectious mononucleosis in regard to complications and associated conditions. MAIN TEXT: In the present review, these included three early complications; hepatitis, splenic rupture and airway compromise, as well as possible late conditions; lymphoproliferative cancers, multiple sclerosis, rheumatoid arthritis, and chronic active Epstein-Barr virus infection. This review thus highlights recent advances in the understanding of Epstein-Barr virus pathogenesis, focusing on management, acute complications, referral indications and potentially associated conditions. CONCLUSIONS: Hepatitis is a common and self-limiting early complication to infectious mononucleosis and should be monitored with liver tests in more symptomatic cases. Splenic rupture is rare. Most cases are seen within 3 weeks after diagnosis of infectious mononucleosis and may occur spontaneously. There is no consensus on the safe return to physical activities, and ultrasonic assessment of spleen size may provide the best estimate of risk. Airway compromise due to tonsil enlargement is encountered in a minority of patients and should be treated with systemic corticosteroids during hospitalization. Association between lymphoproliferative cancers, especially Hodgkin lymphoma and Burkitt lymphoma, and infectious mononucleosis are well-established. Epstein-Barr virus infection/infectious mononucleosis as a risk factor for multiple sclerosis has been documented and may be linked to genetic susceptibility. Chronic active Epstein-Barr virus infection is rare. However, a general practitioner should be aware of this as a differential diagnosis in patients with persisting symptoms of infectious mononucleosis for more than 3 months.

Infections of the Oropharynx.

This article reviews the presentation, diagnosis, and management of common and "can't miss" infections of the oropharynx, including streptococcal pharyngitis, infectious mononucleosis, peritonsillar abscess, retropharyngeal abscess, and epiglottitis.

Mononucleosis-related fatigue: supplementary management with Robuvit®.

BACKGROUND: Infectious mononucleosis (IM) is a common disease of adolescents and young adults, characterized by a specific triad of symptoms represented by fever, sore throat and lymphadenopathy. IM may also affect older adults, with different, more intense signs and symptoms such as fatigue, general malaise, and diffuse body pain. The aim of this four-week-registry study was to evaluate the effects of Robuvit® supplementation on the main consequences of mononucleosis, particularly fatigue, in otherwise healthy adults. METHODS: All patients enrolled in this registry study experienced an episode of IM characterized by fatigue, a general feeling of unwellness, diffuse body and muscular pain, leukocytosis, and high levels of oxidative stress, at least 2 to 4 weeks prior to inclusion. Fever had already resolved at inclusion. All included patients were positively tested for the Epstein-Barr virus (EBV). Subjects were divided in two groups: those receiving the standard management (SM, N.=26; vitamin B, C, and D, balanced healthy diet, regular sleeping schedule, physical activity, 2 mg copper), and those treated with SM plus Robuvit® (N.=24) supplementation (300 mg/day). RESULTS: Supplementation with Robuvit® was safe, overall tolerability was good, and no side effects were reported. All patients completed the four-week treatment. After 4 weeks of treatment, a significant reduction in the rate of symptoms was evident in the Robuvit® group compared to the control group (P<0.05). CONCLUSIONS: Supplementation with Robuvit® is safe, well tolerated, and effective in controlling oxidative stress levels and improving fatigue and other symptoms related to IM episodes during the convalescence period.

An infant with concurrent serotype 6C invasive pneumococcal disease and infectious mononucleosis.

Streptococcus pneumoniae is a main causative agent of serious invasive bacterial infections. However, concurrent infection with invasive pneumococcal disease (IPD) and viral infectious mononucleosis (IM) is rare. We report an infant with serotype 6C infection causing IPD occurring simultaneously with IM. A previously healthy 11-month-old girl referred to our hospital because of fever, leukopenia, and elevated C-reactive protein presented to us with disturbance of consciousness, tachycardia, tachypnea and agranulocytosis. Other findings included tonsillitis with purulent exudates and white spots, bilateral cervical adenopathy, and hepatosplenomegaly. We diagnosed her illness as sepsis and administered a broad-spectrum antibiotic, an antiviral agent, and granulocyte transfusions. After treatment was initiated, fever gradually decreased and general condition improved. IPD was diagnosed based upon isolation of S. pneumoniae of serotype 6C from blood cultures obtained on admission. Concurrently the girl had IM, based upon quantitation of Epstein-Barr viral DNA copies in blood and fluctuating serum antibody titers. Although simultaneous IPD and IM is a rare occurrence, this possibility is important to keep in mind.

Horner syndrome in glandular fever: a case report.

OBJECTIVE: This study aimed to present and discuss the case of a patient with known glandular fever who presented with Horner syndrome. CASE REPORT: A 35-year-old patient with known glandular fever developed acute unilateral Horner syndrome, a previously undescribed complication of this common illness. Magnetic resonance imaging and magnetic resonance angiography showed that enlarged intra-carotid sheath lymphoid tissue was likely to be the underlying cause of sympathetic nerve disruption. The case is described, the anatomy of the sympathetic chain is discussed and possible alternative pathophysiological mechanisms are reviewed. CONCLUSION: This is the first report in the worldwide literature of Horner syndrome arising as a result of compression from enlarged lymph nodes in glandular fever.

[Acute oliguric renal failure and haemolytic anaemia following infectious mononucleosis]. / Akut nyresvigt og hæmolytisk anæmiefter infektiøs mononukleose.

A 19-year-old man was admitted to hospital due to fatigue, nausea, abdominal pain and faint. He was pale and icteric, awake with sufficient respiration and circulation. He had infectious mononucleosis complicated with acute oliguric renal failure and severe haemolytic anaemia with a positive Coombs test. He had a cold agglutinin syndrome. The treatment comprised intermittent haemodialysis, plasmapheresis and heating. He recovered completely after two months.

Haemolytic anaemia: don't leave it out in the cold.

This clinical case highlights the diagnostic odyssey of an adolescent girl presenting to A&E with non-specific headaches and chest pain. The case will describe the steps in decision making from admission to follow-up.

Common questions about infectious mononucleosis.

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 mm3. 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.