[Cold agglutinin syndrome associated with infectious mononucleosis: A case report]. / Síndrome por aglutininas frías secundario a mononucleosis infecciosa: reporte de un caso.

Background: Cold agglutinin syndrome (CAS) is a hemolytic anemia mediated by antibodies, mainly IgM, whose maximum activity occurs at 4 °C. It happens secondary to infectious, autoimmune or neoplastic diseases, due to the formation of antibodies that cross-react against erythrocyte antigens, particularly of the I system. Here, we describe a case of CAS associated to Epstein-Barr virus (EBV) reactivation in a patient with primary human immunodeficiency virus (HIV) infection. Clinical case: 22-year old man with no medical history, hospitalized due to mononucleosis and anemic syndrome. Hemoglobin of 3.7 g/dL and elevation of lactate dehydrogenase were documented. In the peripheral blood smear it was observed spherocytosis, polychromasia and nucleated erythrocytes. EBV infection was confirmed with serology and viral load, as well as seronegative HIV infection with positive viral load. The C3d monospecific direct antiglobulin test was positive and an irregular antibody screening revealed the presence of an anti-I antibody. The patient received transfusion support and conservative treatment, with remission of the symptoms 2 weeks after admission. Conclusions: Cold agglutinin syndrome is a rare, potentially fatal complication of infectious mononucleosis, which should be considered in the face of findings suggestive of hemolysis in order to initiate support measures in a timely manner.

Introducción: el síndrome por aglutininas frías (SAF) es una anemia hemolítica mediada por anticuerpos principalmente de tipo IgM, cuya máxima actividad se da a 4 °C. Se presenta en el contexto de enfermedades infecciosas, autoinmunes o neoplásicas por la formación de anticuerpos que tienen reacción cruzada contra antígenos eritrocitarios, particularmente del sistema I. En este trabajo presentamos un caso de SAF asociado a reactivación del virus de Epstein-Barr (VEB) en un paciente con primoinfección por el virus de la inmunodeficiencia humana (VIH). Caso clínico: hombre de 22 años, sin antecedentes patológicos, hospitalizado por síndrome mononucleósico y anémico. Presentó hemoglobina de 3.7 g/dL y elevación de lactato deshidrogenasa. En el frotis de sangre periférica se observó esferocitosis, policromasia y eritrocitos nucleados. Se confirmó infección por VEB con serología y carga viral, así como infección por VIH seronegativa, con carga viral positiva. La prueba de antiglobulina directa monoespecífica a C3d fue positiva y el rastreo de anticuerpos irregulares demostró un anticuerpo anti-I. El paciente recibió soporte transfusional y tratamiento conservador, con remisión del cuadro a las 2 semanas de su ingreso. Conclusiones: el SAF es una complicación poco frecuente de la mononucleosis infecciosa, potencialmente mortal, la cual debe ser considerada ante hallazgos sugestivos de hemólisis con la finalidad de iniciar medidas de soporte de forma oportuna.

Pelvic inflammatory disease associated with cytomegalovirus infection in an immunocompetent adult: Case report and literature review.

Pelvic inflammatory disease associated with cytomegalovirus infection in immunocompetent adults might be difficult to diagnose because of the rarity and relatively inconspicuous symptoms of infectious mononucleosis. Even if the main complaint is lower abdominal pain, careful search for symptoms latent outside the abdomen could lead to the diagnosis.

Cytokine Storm Syndromes Associated with Epstein-Barr Virus.

Epstein-Barr virus (EBV) is a ubiquitous and predominantly B cell tropic virus. One of the most common viruses to infect humans, EBV, is best known as the causative agent of infectious mononucleosis (IM). Although most people experience asymptomatic infection, EBV is a potent immune stimulus and as such it elicits robust proliferation and activation of the B-lymphocytes it infects as well as the immune cells that respond to infection. In certain individuals, such as those with inherited or acquired defects affecting the immune system, failure to properly control EBV leads to the accumulation of EBV-infected B cells and EBV-reactive immune cells, which together contribute to the development of often life-threatening cytokine storm syndromes (CSS). Here, we review the normal immune response to EBV and discuss several CSS associated with EBV, such as chronic active EBV infection, hemophagocytic lymphohistiocytosis, and post-transplant lymphoproliferative disorder. Given the critical role for cytokines in driving inflammation and contributing to disease pathogenesis, we also discuss how targeting specific cytokines provides a rational and potentially less toxic treatment for EBV-driven CSS.

Effects of ganciclovir combined with recombinant human interferon-α on clinical efficacy and immune function in children with infectious mononucleosis.

Objective: To evaluate the effects of ganciclovir combined with recombinant human interferon on clinical efficacy and immune function of children with infectious mononucleosis(IM). Methods: This was a retrospective study. Children (n=120) with IM hospitalized in Beijing Children's Hospital Affiliated to Capital Medical University Baoding Hospital from January 2020 to January 2022 were selected and randomly divided into study group and control group((n=60). Patients in the control group were treated with ganciclovir by intravenous infusion, and patients in the study group were given ganciclovir+recombinant human interferon-α1b. The time for eliminating clinical symptoms, the levels of inflammatory cytokines, immune function condition and T-lymphocyte subsets between the two groups were compared and analyzed. Results: After treatment, the time for body temperature returned to normal, time for recovery from cervical lymphadenopathy, time for recovery from hepatosplenomegaly and time for disappearance of angina and oral mucosal congestion in the study group were significantly shorter than those in the control group(p= 0.00); after treatment, the levels of TNF-a and IL-6 in the study group were significantly lower than those in the control group; the indexes of CD3+ and CD8+ in the study group were significantly lower than those in the control group; after treatment, the levels of CD4+ and CD4+/CD8+ in the study group were significantly higher than those in the control group. Conclusion: Ranciclovir combined with recombinant human interferon-α1b, rapid improvements of clinical symptoms, significantly decreased inflammatory cytokines, improved T-lymphocyte function and no significant increase in adverse drug reactions were found in children with IM.

Acute Appendicitis in the Setting of Infectious Mononucleosis: A Case Report.

Infectious mononucleosis (IM) is a viral illness caused by the Epstein-Barr virus that typically manifests with pharyngitis, lymphadenopathy, and fatigue. In rare cases, IM can cause acute appendicitis. We present the case of an 18-year-old female who arrived at the emergency department with worsening abdominal pain and an ongoing cough. Initial imaging showed a questionably dilated appendix, and a follow-up examination revealed cervical lymphadenopathy. She later returned to the ED with severe abdominal pain, clinical signs of acute appendicitis, and a positive monospot test, which led to an appendectomy. This case illustrates the need for complete history taking and thorough physical examination in patients with acute appendicitis, as their condition may be due to an atypical underlying cause.

Posttransplant Lymphoproliferative Disorder in a Patient With Alpha-1 Antitrypsin Deficiency: A Case Report.

A 13-year-old male with a past medical history of receiving a whole liver transplant secondary to alpha-1 antitrypsin deficiency (AATD) with subsequent inferior vena cava thrombosis nine years prior presented to the emergency department with abdominal distension, shortness of breath, coughing, and left superficial cervical lymphadenopathy. He had seen his pediatrician the day before where he tested negative for group A Streptococcus, influenza, and severe acute respiratory syndrome coronavirus 2. Additionally, the patient reported having elevated liver function tests noted from the results of lab tests taken earlier that day. The patient was admitted to the hospital. While at the hospital, a lymph node biopsy was performed, and pathology from that biopsy revealed infectious mononucleosis-like nondestructive posttransplant lymphoproliferative disorder (PTLD). Due to the patient's liver transplant nine years prior, the patient was on an immunosuppressant medication: tacrolimus 2 mg. To treat the PTLD, the tacrolimus was reduced, then stopped, and then subsequently restarted at 1 mg. He also was given ganciclovir and prednisone. Two months after recovering from the PTLD, the patient's Epstein-Barr-virus (EBV) viral load continued to fluctuate, and he was treated with three doses of the monoclonal antibody drug rituximab. After treatment with rituximab, his EBV viral load remained stable. This case report gives insight into the treatment of PTLD and can serve as a reminder to be aware of the possibility of PTLD in a pediatric patient with AATD multiple years after a transplant.

Histopathology of peritonitis due to infectious mononucleosis with background Chlamydia trachomatis infection: A case report and literature review.

Epstein-Barr virus (EBV) is a major cause of infectious mononucleosis (IM), characterized by fever, fatigue, sore throat, lymphadenopathy, atypical lymphocytosis, and elevated liver enzymes. However, ascites is a rare complication associated with IM. We present a rare case of IM with ascites and peritonitis in a patient who underwent a peritoneal biopsy. A 20-year-old woman presented with fatigue and abdominal distension. Laboratory examination revealed atypical lymphocytes in peripheral blood (54%) and elevated liver enzymes. EBV serological tests revealed a recent primary infection (EBV VCA IgM 1:160). Computed tomography revealed moderate ascites and peritonitis. Adenocarcinoma was suspected based on the ascites' cytology. Considering possible complications of IM and adenocarcinoma, a laparoscopic biopsy was performed. Histological findings of biopsy specimens from the peritoneum, omentum, and fimbria of the fallopian tube demonstrated severe inflammatory cell infiltration and focal aggregation of large EBV-encoded RNA-1 (EBER1)-positive B cells, mimicking EBV-positive polymorphous B-cell lymphoproliferative disorder. Furthermore, intracytoplasmic inclusion bodies of Chlamydia trachomatis were observed by immunohistochemistry. Real-time polymerase chain reaction detected C. trachomatis in cervical secretions. Two months after laparoscopy, ascites decreased, and the diagnosis was IM-associated peritonitis with C. trachomatis infection. IM should be considered as a differential diagnosis in young patients with ascites.

Spontaneous Splenic Rupture Secondary to Infectious Mononucleosis.

Spontaneous splenic rupture (SSR) is a relatively rare but potentially lethal complication of infectious mononucleosis (IM). While SSR is extremely rare in patients with proven IM, it is the most lethal complication of the infection (9% mortality rate) and can present completely asymptomatically or with abdominal pain and hemodynamic instability. As adolescents and young adults are the most affected population group, with this case report, we intend to raise the vigilance of any doctor treating those patients in the emergency department. We present the case of a 16-year-old patient with an atraumatic splenic rupture and hemoperitoneum secondary to an Epstein-Barr virus (EBV) infection. The patient underwent an exploratory laparotomy, and a splenectomy was performed. This case demonstrates that, even if SSR in patients with IM is extremely rare, it should always be considered in a patient with a relevant clinical presentation.

Infectious Mononucleosis Revealed by Non-steroidal Anti-inflammatory Drug: A First Clinical Report.

Infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV), is a common viral illness among adolescents and young adults. IM typically presents with symptoms such as fever, lymphadenopathy, and pharyngitis. We present a case of a 32-year-old woman who developed a maculopapular rash following ibuprofen administration, revealing an underlying undiagnosed IM. Laboratory investigations confirmed EBV infection. This represents the first documented case linking non-steroidal anti-inflammatory drugs (NSAIDs) to IM presentation. Awareness of this association is crucial for timely diagnosis and management, especially when evaluating patients with unexplained skin reactions to medications.

Marked gallbladder wall thickening caused by Epstein-Barr virus-induced infectious mononucleosis.

Key Clinical Message: In patients with symptoms of viral infection and marked thickening of the gallbladder wall, it is important to suspect acalculous cholecystitis due to Epstein-Barr virus-induced infectious mononucleosis. Abstract: A 35-year-old Japanese man presented with fever, abdominal right upper quadrant pain, and liver dysfunction. Positive immunoglobulin M and -G antibodies and negative nuclear antigen for Epstein-Barr virus were observed. Abdominal ultrasonography revealed a markedly thickened gallbladder wall. Acalculous cholecystitis due to Epstein-Barr virus-induced infectious mononucleosis was diagnosed.

Histone methylation in Epstein-Barr virus-associated diseases.

Epstein-Barr virus (EBV) infection is linked to various human diseases, including both noncancerous conditions like infectious mononucleosis and cancerous diseases such as lymphoma and nasopharyngeal carcinoma. After the initial infection, EBV establishes a lifelong presence and remains latent in specific cells. This latent infection causes changes in the epigenetic marks known as histone methylation. Many studies have examined the role of histone methylation in different EBV-associated diseases, and understanding how EBV affects histone methylation can help us identify potential targets for epigenetic therapies. This review focuses on the research progress made in understanding histone methylation in well-studied EBV-associated diseases, intending to provide insights into potential strategies based on histone methylation to combat EBV-related ailments.

This review focuses on histone methylation in EBV-associated diseases, offering potential strategies to combat EBV-related ailments. #EBV #histonemethylation #epigenetics #medicalresearch.

Two cases of misleading Epstein-Barr virus infection and the role of EBV-DNA.

Two atypical cases of infectious mononucleosis in two teenagers with initially negative serology and non-evocative blood examinations are reported. The first patient had recently traveled to Africa, and Epstein-Barr virus negative serology led us to make many extensive investigations. The second patient complained of asthenia for a month, and PET/CT was performed to suspicion of lymphoma. PET scan revealed hypermetabolic lymph nodes in the supradiaphragmatic and subdiaphragmatic stations, along with18F-FDG uptake in the spleen and pharynx, raising more suspicion of lymphoma. Fortunately, Epstein-Barr virus DNA testing was performed and turned positive in both cases, and Epstein-Barr virus serology subsequently became positive. Diagnosing EBV infection can be challenging in rare cases, as EBV-specific serology may be negative in the early stages and confounding factors may be present. Therefore, Epstein-Barr virus DNA testing should be considered early in the diagnostic algorithm to prevent unnecessary investigations in similar cases.

Evaluation of novel Epstein-Barr virus-derived antigen formulations for monitoring virus-specific T cells in pediatric patients with infectious mononucleosis.

BACKGROUND: Infection with the Epstein-Barr virus (EBV) elicits a complex T-cell response against a broad range of viral proteins. Hence, identifying potential differences in the cellular immune response of patients with different EBV-associated diseases or different courses of the same disorder requires interrogation of a maximum number of EBV antigens. Here, we tested three novel EBV-derived antigen formulations for their ability to reactivate virus-specific T cells ex vivo in patients with EBV-associated infectious mononucleosis (IM). METHODS: We comparatively analyzed EBV-specific CD4+ and CD8+ T-cell responses to three EBV-derived antigen formulations in 20 pediatric patients during the early phase of IM: T-activated EBV proteins (BZLF1, EBNA3A) and EBV-like particles (EB-VLP), both able to induce CD4+ and CD8+ T-cell responses ex vivo, as well as an EBV-derived peptide pool (PP) covering 94 well-characterized CD8+ T-cell epitopes. We assessed the specificity, magnitude, kinetics, and functional characteristics of EBV-specific immune responses at two sequential time points (v1 and v2) within the first six weeks after IM symptom onset (Tonset). RESULTS: All three tested EBV-derived antigen formulations enabled the detection of EBV-reactive T cells during the early phase of IM without prior T-cell expansion in vitro. EBV-reactive CD4+ and CD8+ T cells were mainly mono-functional (CD4+: mean 64.92%, range 56.15-71.71%; CD8+: mean 58.55%, range 11.79-85.22%) within the first two weeks after symptom onset (v1) with IFN-γ and TNF-secreting cells representing the majority of mono-functional EBV-reactive T cells. By contrast, PP-reactive CD8+ T cells were primarily bi-functional (>60% at v1 and v2), produced IFN-γ and TNF and had more tri-functional than mono-functional components. We observed a moderate correlation between viral load and EBNA3A, EB-VLP, and PP-reactive CD8+ T cells (rs = 0.345, 0.418, and 0.356, respectively) within the first two weeks after Tonset, but no correlation with the number of detectable EBV-reactive CD4+ T cells. CONCLUSIONS: All three EBV-derived antigen formulations represent innovative and generic recall antigens suitable for monitoring EBV-specific T-cell responses ex vivo. Their combined use facilitates a thorough analysis of EBV-specific T-cell immunity and allows the identification of functional T-cell signatures linked to disease development and severity.

[The Role of Notch Signaling Pathway in Adult Patients with Epstein-Barr Virus-induced Infectious Mononucleosis].

OBJECTIVE: To investigate the changes of Notch signaling molecules and Th22 cells in adult patients with infectious mononucleosis (IM), and assess the regulatory function of Notch signaling inhibition to Th22 cells. METHODS: Forty-two IM patients and twenty-one healthy controls were enrolled in this study. Their peripheral blood was collected, from which plasma and peripheral blood mononuclear cells (PBMCs) were isolated. Plasma interleukin (IL)-17 and IL-22 were measured by enzyme-linked immunosorbent assay. The percentages of CD3+ CD4+ IL-17+ Th17 cells and CD3+ CD4+ IL-22+ Th22 cells were investigated by flow cytometry. The mRNA relative levels corresponding to Th17 transcription factor retinoic acid related orphan receptor γt (RORγt), Th22 transcription factor aryl hydrocarbon receptor (AhR), and Notch signaling pathway molecules (including Notch receptors, Notch ligands, Notch downstream molecules) were semi-quantified by real-time PCR. CD4+ T cells were purified and stimulated with γ-secretase inhibitor (GSI). Cellular proliferation, Th17 and Th22 percentage, IL-17 and IL-22 secretion, transcription factor mRNA were measured in response to GSI stimulation. RESULTS: The relative expression levels of Notch1 and Notch2 mRNA in PBMCs of IM group were 13.58±3.18 and 4.73±1.16, respectively, which were significantly higher than 1.09±0.12 and 1.07±0.15 in PBMCs of control group (both P < 0.001). However, there were no significant differences in relative expression levels of Notch3 and Notch4 mRNA between IM group and control group (P >0.05). The relative expression levels of Notch ligands (including DLL1 and Jagged1 ) mRNA and Notch downstream molecules (including Hes1, Hes5, and Hey1 ) were increased in IM group compared with control group (all P < 0.001). In IM group, the Th17 and Th22 percentage were 5.03%±1.15% and 4.48%±1.29%, respectively, which were both higher than 4.36%±0.82% and 3.83%±0.55% in control group (both P < 0.05). In IM group, the IL-17 and IL-22 level were (301.1±53.82) and (101.2±16.45) pg/ml, respectively, which were both higher than (237.2±72.18) and (84.75±11.83) pg/ml in control group (both P < 0.001). In IM group, the relative expression levels of RORγt and AhR mRNA were 1.25±0.22 and 1.21±0.12, respectively, which were both higher than 0.99±0.15 and 1.04±0.11 in control group (both P < 0.001). There were no remarkable differences in CD4+ T cell proliferation, Th17 percentage, IL-17 secretion, and relative expression level of RORγt mRNA between cells with GSI stimulation and without GSI stimulation (P >0.05). GSI stimulation reduced Th22 percentage, IL-22 secretion, and relative expression level of AhR mRNA compared with non-stimulation (all P < 0.05). CONCLUSION: Notch signaling pathway regulates IL-22 secretion by CD4+ T cells via AhR in IM patients. Notch-AhR-Th22 pathway may take part in the pathogenesis of IM.

Seroprevalence and characterization of Epstein-Barr virus exposure among paediatric population.

The study explored Epstein Barr Virus (EBV) exposure in 244 children using EBV-specific serology. Seroprevalence of EBV was 75-80%. Past infection and primary infection were observed in 52.04% & 8.6% respectively, whereas 23.36% showed no serological evidence of exposure to EBV. Age-stratification suggested maternal antibodies may have protected infants till 6 months of age, while the 1-3 year age group showed maximum primary infection and the 6 months to 1 year group showed the maximum susceptible group to EBV primary infection. There is a paucity of literature about EBV in India and further research is required for a better understanding of EBV pathogenesis and its clinical implications in Indian children.

Severe Upper Airway Obstruction in a Patient With Infectious Mononucleosis.

Infectious mononucleosis (IM) is a clinical disease caused by the Epstein-Barr virus (EBV). Common presenting symptoms include sore throat, lymph node enlargement, fever, and malaise. Although severe upper airway obstruction is uncommon, it is a potentially fatal complication that requires immediate intervention. We describe the case of an 18-year-old Hispanic man who presented with a progressive sore throat and difficulty speaking, requiring endotracheal intubation for airway protection. CT images showed diffuse swelling of Waldeyer's tonsillar ring, multiple enlarged lymphadenopathies, and splenomegaly. Acute EBV infection was confirmed considering clinical presentation and using the heterophile antibody, anti-nuclear and anti-viral capsid antigens, and quantitative PCR. The patient was managed with ventilatory support, empirical antibiotic therapy, and systemic corticosteroids, achieving a positive outcome. Our case illustrates the use of corticosteroids in managing severe upper airway obstruction complicating IM.

Splenic Infarction Due to Epstein-Barr Virus: A Case Report and Literature Review.

Splenic infarction is a rare and likely underdiagnosed complication of Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM). Here, we describe an 18-year-old Guyanese male with persistent severe left-sided abdominal pain found to be EBV positive and have a large splenic infarct, along with a transient decrease in protein C, protein S, and antithrombin III activity levels. He was treated with supportive care and anticoagulated with heparin and apixaban. We review prior reports and perspectives on underlying pathophysiology, diagnosis, and the management of these cases, which likely do not require anticoagulation but may be considered on a per-case basis.

Infectious mononucleosis due to Epstein-Barr virus reactivation in an immunocompromised 60-year-old patient with COVID-19.

Epstein-Barr virus (EBV) reactivation in COVID-19 patients has been reported, but studies on its clinical significance are lacking. We herein report the occurrence of infectious mononucleosis (IM) due to EBV reactivation in a 60-year-old man with rheumatoid arthritis being treated with methotrexate and tocilizumab. The patient presented with a fever and tested positive for COVID-19. Laboratory findings revealed an increased atypical lymphocyte count, decreased platelet count, and elevated liver enzyme levels. Flow cytometry showed predominant expansion of reactive T cells. EBV reactivation was confirmed using real-time polymerase chain reaction. The patient was treated with remdesivir, and clinical improvement was observed after 10 days of treatment. Follow-up showed a gradual decrease in the EBV-DNA load with no recurrence of atypical lymphocytes. These findings suggest that COVID-19 in immunocompromised patients may lead to unexpected EBV reactivation and IM, even for patients outside the age at which IM is likely to occur.

Bilateral Sialadenitis as an Uncommon Initial Manifestation of Infectious Mononucleosis: A Case Report.

Sialadenitis has rarely been reported in patients with infectious mononucleosis (IM). Our patient was a 22-year-old man who presented with bilateral swelling of the parotid and submandibular glands, a fever, malaise, and splenomegaly. Laboratory tests revealed an increased percentage of atypical lymphocytes in the leukocyte fraction. Serological testing for antibodies against Epstein-Barr virus (EBV) revealed an acute infection pattern. The patient was diagnosed with sialadenitis associated with IM caused by EBV infection. With symptomatic treatment, the salivary gland swelling completely resolved within a week. This case suggests that EBV-induced IM should be included in the differential diagnosis of diffuse sialadenitis with elevated atypical lymphocyte counts.

The Impact of Infectious Mononucleosis History on the Risk of Developing Lymphoma and Nasopharyngeal Carcinoma: a Retrospective Large-Scale Cohort Study using National Health Insurance Data in South Korea.

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 (HR=5.32, 95% CI 3.208‒8.82, p<0.001) and NPC (HR=7.116, 95% CI 1.617‒31.314, 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 1.858‒2.663, 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.