[Epstein-Barr virus-associated lymphoproliferative disorders after BNT162b2 mRNA COVID-19 vaccination].

Epstein-Barr virus-associated lymphoproliferative disorders (EBV-LPD) is a rare disease characterized by persistent or recurrent inflammation accompanied by EBV infection of T or NK cells that is not self-limiting, and it is fatal, if untreated. After receiving the first dose of the BNT162b2 mRNA COVID-19 vaccine, a 79-year-old male presented to the hospital with a 2-week history of fever. Laboratory results indicated pancytopenia, elevated liver transaminase levels, hyperferritinemia, and hypofibrinogenemia. Computed tomography revealed hepatosplenomegaly, but lymphadenopathy was not observed. A bone marrow biopsy, a random skin biopsy, and a liver biopsy revealed no malignancy, but an infectious evaluation revealed EBV viremia (5.19 Log IU/ml). Flow cytometry and RT-PCR revealed that the EBV genome was localized in NK cells, suggesting the diagnosis of EBV-NK-LPD. We administered prednisolone, intravenous immunoglobulin, and etoposide, but the EBV-DNA load failed to decrease, and he died 2 months later. Recently, case reports of COVID-19 vaccination-related hemophagocytic lymphohistiocytosis have been published. Although the mechanisms and risk factors for EBV-LPD after BNT162b2 mRNA COVID-19 vaccination remain unknown, it is important to note the possibility of reactivation of EBV after COVID-19 vaccination to initiate early and targeted therapy.

SARS-CoV-2-fertozés okozta Kikuchi-Fujimoto-betegség sikeres gyógyítása.

The Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis) is an autolimited process, which can be caused by viral agents like Epstein-Barr virus, human herpes virus, HIV, B19 parvovirus, paromyxoviruses, SARS-CoV-2, Toxoplasma and Yersinia. The correct diagnosis is based on histological findings. A 45-year-old female patient presented in our ambulatory room with a unilateral neck mass, fever, dysphonia and dysphagia. The patient was double-tested positive for SARS-CoV-2 approximately 1 month before the symptoms started. Before examination, the nasopharyngeal rapid test for SARS-CoV-2 resulted negative. After hospitalization, intravenous antibiotic (Augmentin, 3 × 1.2 g; Klion, 2 × 100 mg) and steroid (Solu-Medrol, 2 × 125 mg) therapy were administered. The neck and chest CT described a right-sided retropharyngeal abscess with bilateral neck lympadenopathy. Urgent tracheotomy, neck dissection and lymph node biopsy were made. The intraoperative findings excluded the presence of the abscess. The histological findings confirmed the necrotizing histiocytic lymphadenitis. Despite of the fact that the Kikuchi-Fujimoto disease is autolimited, we can see that, in this particular case, the lymphadenopathy after the SARS-CoV-2 infection caused a life-threatening situation. The formed extratissular liquid imitated the image of a retropharyngeal abscess. In the searched worldwide literature, similar intervention for this type of process was not described. Tracheotomy, neck dissection and removing the lymph nodes as ,,trigger zones" caused the full recovery of the patient. In the future, we consider important proving and clarifying the correlation between SARS-CoV-2 and Kikuchi-Fujimoto disease. Orv Hetil. 2022; 163(27): 1061-1065.

Utility of Epstein-Barr Virus DNA in Nasopharynx Swabs as a Reflex Test to Triage Seropositive Individuals in Nasopharyngeal Carcinoma Screening Programs.

BACKGROUND: Epstein-Barr virus (EBV) DNA detection in the nasopharynx is considered a biomarker for nasopharyngeal carcinoma (NPC). We evaluated its performance as a reflex test to triage EBV seropositives within an NPC screening program in China. METHODS: The study population was embedded within an ongoing NPC screening trial and included 1111 participants who screened positive for anti-EBV VCA (antibodies against EBV capsid antigens)/EBNA1 (EBV nuclear antigen1)-IgA antibodies (of 18 237 screened). Nasopharynx swabs were collected/tested for EBNA1 gene EBV DNA load. We evaluated performance of EBV DNA in the nasopharynx swab as a reflex test to triage EBV serological high-risk (those referred to endoscopy/MRI) and medium-risk (those referred to accelerated screening) individuals. RESULTS: By the end of 2019, we detected 20 NPC cases from 317 serological high-risk individuals and 4 NPC cases from 794 medium-risk individuals. When used to triage serological high-risk individuals, nasopharynx swab EBV DNA was detected in 19/20 cases (positivity rate among cases: 95.0%; 95% CI, 75.1%-99.9%), with a referral rate of 63.4% (201/317, 95% CI, 57.8%-68.7%) and NPC detection rate among positives of 9.5% (19/201, 95% CI, 5.8%-14.4%). The performance of an algorithm that combined serology with triage of serology high-risk individuals using EBV DNA testing yielded a sensitivity of 72.4% (95% CI, 3.0%-81.4%) and specificity of 97.6% (95% CI, 97.2%-97.9%). When used to triage EBV serological medium-risk individuals, the positivity rate among cases was 75.0% (95% CI, 19.4%-99.4%), with a referral rate of 61.8% (95% CI, 58.4%-65.2%) and NPC detection rate among positives of 0.6% (95% CI, 0.1%-1.8%). CONCLUSIONS: Nasopharynx swab EBV DNA showed promise as a reflex test to triage serology high-risk individuals, reducing referral by ca. 40% with little reduction in sensitivity compared to a serology-only screening program.

Parkinsonism associated with viral infection.

There are several known causes of secondary parkinsonism, the most common being head trauma, stroke, medications, or infections. A growing body of evidence suggests that viral agents may trigger parkinsonian symptoms, but the exact pathological mechanisms are still unknown. In some cases, lesions or inflammatory processes in the basal ganglia or substantia nigra have been found to cause reversible or permanent impairment of the dopaminergic pathway, leading to the occurrence of extrapyramidal symptoms. This chapter reviews current data regarding the viral agents commonly associated with parkinsonism, such as Epstein Barr virus (EBV), hepatitis viruses, human immunodeficiency virus (HIV), herpes viruses, influenza virus, coxsackie virus, and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). We present possible risk factors, proposed pathophysiology mechanisms, published case reports, common associations, and prognosis in order to offer a concise overview of the viral spectrum involved in parkinsonism.

Chronic active Epstein-Barr exacerbated by COVID-19 co-infection.

A 60-year-old Hispanic female was admitted with recurrent fevers, altered mental status, lymphadenopathy, hepatosplenomegaly, and pancytopenia. Initially, sepsis was presumed because of recurrent urinary tract infection with extended-spectrum beta-lactamase Escherichia coli. Despite appropriate therapy, her clinical condition continued to decline. An extensive workup was obtained to determine the source of her ailments. Bone marrow biopsy was negative for leukemia, lymphoma, and myelodysplastic syndrome; fluorescence in situ hybridization and a cytogenetic panel were normal; a lumbar puncture was negative. However, peripheral blood was remarkable for elevated titers for Epstein-Barr virus (EBV) consistent with chronic active EBV. Treatment with valganciclovir showed early positive results, but the patient became co-infected with COVID-19, and her EBV titer increased again, resulting in a precipitous health decline and death.

Adenovirus Hepatitis in Immunocompetent Adults.

A 35-year-old female with no medical history presented with fever. Laboratory work was normal except for elevated liver function test (LFT): alkaline phosphatase (AP) (296), aspartate transaminase (AST) (343), alanine transaminase (ALT) (378), and international normalized ratio (INR) (1.23). Ultrasound liver was normal. Infectious workup was negative for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes simplex virus (HSV), and COVID-19. Similarly, autoimmune hepatitis, Wilson, and alpha-1 antitrypsin workup were negative. She reported taking Yogi-Kanthika (ayurvedic-proprietary medicine) on/off for seasonal sore throat, yet RUCAM-score was 2 (unlikely a drug induced injury). Respiratory-viral-panel came positive for adenovirus. With supportive treatment, symptoms and LFT trended down, thus, liver biopsy decision was deferred. We believe this is the first reported case of adenovirus hepatitis in an immunocompetent adult. Hence, we suggest that clinicians should consider a refined differential diagnosis for elevated LFT (that includes adenovirus).

Reactivation of EBV and CMV in Severe COVID-19-Epiphenomena or Trigger of Hyperinflammation in Need of Treatment? A Large Case Series of Critically ill Patients.

BACKGROUND: Reactivation of viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are common in critically ill patients and have been described in patients with severe COVID-19. However, it is unclear whether these reactivations are associated with increased mortality and whether targeted treatments are beneficial. METHODS: In a retrospective single-center cohort study, patients with severe COVID-19 treated on our intensive care unit (ICU) were screened for EBV and CMV reactivation as detected by polymerase chain reaction. If present, patient characteristics, temporal connections to severe acute respiratory syndrome coronavirus 2 diagnosis and corticosteroid use, the use of targeted treatments as well as the course of disease and outcome were analyzed. As control group, non-COVID-19 patients with sepsis, treated within the same time period on our ICU, served as control group to compare incidences of viral reactivation. RESULTS: In 19 (16%) of 117 patients with severe COVID-19 treated on our ICU EBV reactivations were identified, comparable 18 (14%) of 126 in the non-COVID-19 control group (P = .672). Similarly, in 11 (9%) of 117 patients CMV reactivations were identified, comparable to the 16 (13%) of 126 in the non-COVID-19 sepsis patients (P = .296). The majority of EBV (58%) and CMV reactivations (55%) were detected in patients under systemic corticosteroid treatment. 7 (37%) of 19 patients with EBV reactivation survived the ICU stay, 2 (29%) of 7 patients with rituximab treatment and 5 (42%) of 12 patients without treatment (P = .568). Five (50%) of 10 patients with CMV reactivation survived the ICU stay, 5 (83%) of 6 patients with ganciclovir treatment and 0 of 4 patients without treatment (P = .048). Follow-up analysis in these patients showed that the initiation of treatment lead to decrease in viral load. CONCLUSION: Critically ill patients with COVID-19 are at a high risk for EBV and CMV reactivations. Whether these reactivations are a cause of hyperinflammation and require targeted treatment remains uncertain. However, in patients with clinical deterioration or signs of hyperinflammation targeted treatment might be beneficial and warrants further studying.

SARS-CoV-2-associated Henoch-Schönlein purpura in a 13-year-old girl.

In the context of the current coronavirus disease 2019 (COVID-19) pandemic, cutaneous lesions are being described. Here, we report on a 13-year-old girl with SARS-CoV-2-associated Henoch-Schönlein purpura and Epstein-Barr virus (EBV) infection. She presented without any respiratory symptoms, only a purpuric skin rash, abdominal pain, low-grade fever, and pharyngitis. Virology tests by polymerase chain reaction (PCR) were positive for SARS-CoV-2 and EBV. The potential association of Henoch-Schönlein purpura and SARS-CoV-2 should be kept in mind in order to reduce the spread of the virus, particularly in children with few respiratory symptoms.

A Case Report of Posttransplant Lymphoproliferative Disorder After AstraZeneca Coronavirus Disease 2019 Vaccine in a Heart Transplant Recipient.

We report a case of a heart transplant recipient who presented with a rapidly growing Epstein-Barr virus (EBV)-positive, diffuse large B-cell lymphoma 7 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. Because of the atypical radiologic presentation, the initial tentative diagnosis was a mediastinal abscess. This observation indicates a potential risk of EBV reactivation after coronavirus disease 2019 (COVID-19) vaccination, which might lead to or aggravate the presentation of posttransplant lymphoproliferative disorder in transplantation patients. Transplant surgeons should be aware of the potential immunomodulatory effects of the COVID-19 vaccination.

Virus-triggered secondary hemophagocytic lymphohistiocytosis.

Primary (familial/hereditary) and secondary (non-familial/hereditary) hemophagocytic lymphohistiocytosis (HLH) are hyperinflammatory and hypercytokinemic syndromes. Secondary HLH includes infection- (eg viral/bacterial/fungal/parasitic) and non-infection- (eg collagen disease or malignancy) related diseases. Viral HLH is the major type among all age groups. Secondary viral HLH and primary HLH must be differentiated carefully because primary HLH can be associated with viral infection(s), and the outcome is dismal without a timely diagnosis and hematopoietic stem cell transplantation (HSCT). Epstein-Barr virus (EBV)-related HLH (EBV-HLH) is the most common type of viral HLH in childhood. For non-EBV-HLH, appropriate treatment of viral infection, followed by immunomodulatory agent(s) such as corticosteroids, intravenous immunoglobulin or cyclosporine A, is usually successful; however, recent SARS-CoV-2-related HLH may become life-threatening. EBV-HLH may occur heterogeneously associated with the primary infection, with chronic active EBV infection or with underlying primary HLH. Although immunomodulatory agent(s) are effective in the majority of EBV-HLH cases, management differs from that of non-EBV-HLH because severe and refractory cases may require etoposide-containing HLH-1994/2004 regimens or other experimental agents. The novel agent, emapalumab (an anti-IFN-γ monoclonal antibody) can be used to treat EBV-HLH cases to avoid the risk of secondary malignancy due to etoposide. Finally, HSCT is required for refractory EBV-HLH cases and can also be curative in some other cases.

Reactive non-sexually related acute genital ulcers associated with COVID-19.

Acute genital ulcers (AGU), known as Lipschütz ulcers, are painful vulvar ulcers typically affecting non-sexually active girls and women. AGU have been associated with viral infections, namely, Epstein-Barr virus (EBV). Here, we describe a case of AGU in the setting of SARS-CoV-2 in a non-sexually active adolescent girl hospitalised for pain control and urinary retention, who failed a course of oral corticosteroids and then improved with colchicine. Testing for herpes simplex virus, EBV and Behcet's syndrome were all negative. Testing for SARS-CoV-2 was positive. COVID-19 increases cytokines such as tumour necrosis factor alpha, which has been shown to affect endothelial cell adhesion and neutrophil chemotaxis, leading to aphthosis.

Case of haemophagocytic lymphohistiocytosis following Epstein-Barr virus infection.

Haemophagocytic lymphohistiocytosis (HLH) is a rare diagnosis that carries a high degree of mortality. We present this case of a previously healthy 22-year-old woman, who was admitted acutely ill to the hospital. One week prior, she had been seen by her primary care physician for fatigue and malaise. At that time, she was noted to have anterior and posterior cervical lymphadenopathy. She was referred to the emergency room and was diagnosed with acute Epstein-Barr virus (EBV) mononucleosis based on her clinical symptoms and positive heterophile antibody test. She was discharged after an uneventful 48-hour stay on the wards. She represented 7 days after discharge with cough, fatigue, nausea, vomiting, epigastric abdominal pain, diarrhoea, weight loss and subjective fevers. She had also reported haematemesis, epistaxis and melaena. Vital signs included temperature 36.9°C, blood pressure 90/50 mm Hg, heart rate 130 beats per minute and respiratory rate 32 breaths per minute. Physical examination was notable for an acutely ill appearing woman with scleral icterus, hepatosplenomegaly and palpable cervical and axillary lymphadenopathy. Complete blood count showed pancytopaenia with haemoglobin 59 g/L (normal 120-160 g/L), white blood cell count 2.7×109/L (normal 4-10.5×109/L) and platelet count 50×109/L (normal 150-450×109/L). The white blood cell count differential included 58% neutrophils (normal 38%-77%) with immature neutrophils in band form elevated at 45% (normal <14%), 16% lymphocytes (normal 20%-48%), 7% monocytes (normal <12%) and no eosinophils (normal <6%). Blood smear revealed anisocytosis, poikilocytosis and hypochromia. Coagulation panel showed elevated levels of d-dimer level at 1.39 µg/mL (normal <0.45 µg/mL), prolonged prothrombin time at 34.4 s (normal 11-15 s), prolonged activated partial thromboplastin time of 55.6 s (normal 25-34 s), prolonged international normalised ratio at 3.31 (normal <1.1) and low fibrinogen 60 mg/dL (normal >200 mg/dL). Lipid panel showed cholesterol at 114 mg/dL (normal 125-200 mg/dL), triglycerides 207 mg/dL (normal 30-150 mg/dL), high-density lipoprotein cholesterol 10 mg/dL (normal 40-60 mg/dL) and low-density lipoprotein cholesterol 63 mg/dL (normal <100 mg/dL). Other lab abnormalities included elevated ferritin of 6513 ng/mL (normal 10-150 ng/mL) and elevated lactate dehydrogenase of 1071 unit/L (normal 95-240 unit/L). Soluble interleukin-2 receptor alpha level was elevated at 60 727 units/mL (normal 223-710 units/mL). Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed abnormal tracer localisation within the paratracheal, hilar, pelvic, abdominal and subcarinal lymph nodes, along with FDG-PET positive hepatosplenomegaly. A bone marrow biopsy showed hypercellular marrow (95% cellularity) with trilineage haematopoiesis, haemophagocytic cells, polytypic plasmacytosis and T-cell lymphocytosis, along with positive latent membrane protein-1 immunohistochemical staining for EBV. EBV quantitative DNA PCR showed >1 million copies. These findings were consistent with a diagnosis of HLH secondary to EBV infection. Despite intense therapy with the HLH-94 protocol, the patient expired from her illness after a prolonged hospital course.

EBV DNA increase in COVID-19 patients with impaired lymphocyte subpopulation count.

OBJECTIVES: The immunologic profile and opportunistic viral DNA increase were monitored in Italian patients with COVID-19 in order to identify markers of disease severity. METHODS: A total of 104 patients infected with SARS-CoV-2 were evaluated in the study. Of them, 42/104 (40.4%) were hospitalized in an intensive care unit (ICU) and 62/104(59.6%) in a sub-intensive care unit (SICU). Human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), Parvovirus B19 and Human Herpesvirus 6 virus reactivations were determined by real-time PCR, and lymphocyte subpopulation counts were determined by flow cytometry. RESULTS: Among opportunistic viruses, only EBV was consistently detected. EBV DNA was observed in 40/42 (95.2%) of the ICU patients and in 51/61 (83.6%) of the SICU patients. Comparing the two groups of patients, the EBV DNA median level among ICU patients was significantly higher than that observed in SICU patients. In parallel, a significant reduction of CD8 T cell and NK count in ICU patients as compared with SICU patients was observed (p<0.05). In contrast, B cell count was significantly increased in ICU patients (p=0.0172). CONCLUSIONS: A correlation between reduced CD8+ T cells and NK counts, EBV DNA levels and COVID-19 severity was observed. Other opportunistic viral infections were not observed. The relationship between EBV load and COVID-19 severity should be further evaluated in longitudinal studies.

Epstein-Barr Virus Versus Novel Coronavirus-Induced Hemophagocytic Lymphohistocytosis: The Uncharted Waters.

Hemophagocytic lymphohistocytosis (HLH) is a hyperinflammatory syndrome characterized by fever, hepatosplenomegaly, and pancytopenia. It may be associated with genetic mutations or viral/bacterial infections, most commonly Epstein-Barr virus (EBV) and cytomegalovirus. As for the novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), also known as COVID-19 (coronavirus disease-2019), the cytokine storm it triggers can theoretically lead to syndromes similar to HLH. In this article, we report a case of a 28-year-old female who presented with high-grade fevers, found to have both SARS-CoV-2 and EBV infections, and eventually began to show signs of early HLH. To our knowledge, this is the first case reported in literature that raises the possibility of SARS-CoV-2-related HLH development.

Child with liver transplant recovers from COVID-19 infection. A case report.

We present the case of a 55-month-old girl who recovered from coronavirus disease 2019 (COVID-19) infection 5 months after undergoing liver transplantation; she had a co-infection with Epstein-Barr virus (EBV). To the best of our knowledge, this is the first case report of a COVID-19 infection in a pediatric patient with liver transplantation. Additionally, this is also the first report of confirmed co-infection between COVID-19 and EBV. On the basis of this case, we suggest that liver transplantation is not associated with COVID-19 symptom severity and development. Moreover, COVID-19 and EBV co-infections do not seem to aggravate the clinical outcome.