How I prevent viral reactivation in high-risk patients.

Preventing viral infections at an early stage is a key strategy for successfully improving transplant outcomes. Preemptive therapy and prophylaxis with antiviral agents have been successfully used to prevent clinically significant viral infections in hematopoietic cell transplant recipients. Major progress has been made over the past decades in preventing viral infections through a better understanding of the biology and risk factors, as well as the introduction of novel antiviral agents and advances in immunotherapy. High-quality evidence exists for the effective prevention of herpes simplex virus, varicella-zoster virus, and cytomegalovirus infection and disease. Few data are available on the effective prevention of human herpesvirus 6, Epstein-Barr virus, adenovirus, and BK virus infections. To highlight the spectrum of clinical practice, here we review high-risk situations that we handle with a high degree of uniformity and cases that feature differences in approaches, reflecting distinct hematopoietic cell transplant practices, such as ex vivo T-cell depletion.

Deciphering the Relationship between SARS-CoV-2 and Cancer.

Some viruses are known to be associated with the onset of specific cancers. These microorganisms, oncogenic viruses or oncoviruses, can convert normal cells into cancer cells by modulating the central metabolic pathways or hampering genomic integrity mechanisms, consequently inhibiting the apoptotic machinery and/or enhancing cell proliferation. Seven oncogenic viruses are known to promote tumorigenesis in humans: human papillomavirus (HPV), hepatitis B and C viruses (HBV, HCV), Epstein-Barr virus (EBV), human T-cell leukemia virus 1 (HTLV-1), Kaposi sarcoma-associated herpesvirus (KSHV), and Merkel cell polyomavirus (MCPyV). Recent research indicates that SARS-CoV-2 infection and COVID-19 progression may predispose recovered patients to cancer onset and accelerate cancer development. This hypothesis is based on the growing evidence regarding the ability of SARS-CoV-2 to modulate oncogenic pathways, promoting chronic low-grade inflammation and causing tissue damage. Herein, we summarize the main relationships known to date between virus infection and cancer, providing a summary of the proposed biochemical mechanisms behind the cellular transformation. Mechanistically, DNA viruses (such as HPV, HBV, EBV, and MCPyV) encode their virus oncogenes. In contrast, RNA viruses (like HCV, HTLV-1) may encode oncogenes or trigger host oncogenes through cis-/-trans activation leading to different types of cancer. As for SARS-CoV-2, its role as an oncogenic virus seems to occur through the inhibition of oncosuppressors or controlling the metabolic and autophagy pathways in the infected cells. However, these effects could be significant in particular scenarios like those linked to severe COVID-19 or long COVID. On the other hand, looking at the SARS-CoV-2─cancer relationship from an opposite perspective, oncolytic effects and anti-tumor immune response were triggered by SARS-CoV-2 infection in some cases. In summary, our work aims to recall comprehensive attention from the scientific community to elucidate the effects of SARS-CoV-2 and, more in general, ß-coronavirus infection on cancer susceptibility for cancer prevention or supporting therapeutic approaches.

Pulmonary lymphomatoid granulomatosis in a patient with long-term use of a tumour necrosis factor-α inhibitor.

A man in his 60s presented with intermittent constitutional symptoms along with waxing and waning chest radiographic abnormalities, eventually leading to a diagnosis of lymphomatoid granulomatosis (LYG). LYG is a rare, progressive Epstein-Barr virus (EBV)-driven lymphoproliferative disease associated with immune dysregulation most commonly involving the lungs. The diagnosis requires tissue biopsy; thus, the decision to pursue tissue sampling with histopathology examination in a timely manner is essential. Currently, there are no established guidelines regarding the treatment of LYG, which varies from cessation of immunosuppressants to immunochemotherapy and usually requires multidisciplinary team discussion.

[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.

Inflammation and Epstein-Barr Virus at the Crossroads of Multiple Sclerosis and Post-Acute Sequelae of COVID-19 Infection.

Recent studies have strengthened the evidence for Epstein-Barr Virus (EBV) as an important contributing factor in the development of multiple sclerosis (MS). Chronic inflammation is a key feature of MS. EBV+ B cells can express cytokines and exosomes that promote inflammation, and EBV is known to be reactivated through the upregulation of cellular inflammasomes. Inflammation is a possible cause of the breakdown of the blood-brain barrier (BBB), which allows the infiltration of lymphocytes into the central nervous system. Once resident, EBV+ or EBV-specific B cells could both plausibly exacerbate MS plaques through continued inflammatory processes, EBV reactivation, T cell exhaustion, and/or molecular mimicry. Another virus, SARS-CoV-2, the cause of COVID-19, is known to elicit a strong inflammatory response in infected and immune cells. COVID-19 is also associated with EBV reactivation, particularly in severely ill patients. Following viral clearance, continued inflammation may be a contributor to post-acute sequelae of COVID-19 infection (PASC). Evidence of aberrant cytokine activation in patients with PASC supports this hypothesis. If unaddressed, long-term inflammation could put patients at risk for reactivation of EBV. Determining mechanisms by which viruses can cause inflammation and finding treatments for reducing that inflammation may help reduce the disease burden for patients suffering from PASC, MS, and EBV diseases.

Association Between Inflammatory Bowel Disease and Viral Infections.

Chronic inflammatory gastrointestinal diseases such as Crohn's disease (CD) and ulcerative colitis (UC) are known as inflammatory bowel disorders (IBD). Patients with inflammatory bowel illnesses are more susceptible to viral infections. In people with IBD, viral infections have emerged as a significant issue. Viral infections are often difficult to identify and have a high morbidity and fatality rate. We reviewed studies on viral infections and IBD, concentrating on Cytomegalovirus (CMV), SARS-CoV-2, Epstein-Barr virus (EBV), enteric viruses, and hepatitis B virus (HBV). Also, the effect of IBD on these viral infections is discussed. These data suggest that patients with IBD are more likely to get viral infections. As a result, practitioners should be aware of the increased risk of viral infections in inflammatory bowel disease patients.

Acquired Von Willebrand Syndrome following a SARS-CoV2 Infection.

Acquired von Willebrand syndrome is a rare clinical entity with approximately 700 cases described in the literature. Different etiologies can be responsible for the occurrence of this condition, including mainly lymphoproliferative and myeloproliferative syndromes, as well as cardiac diseases. Several mechanisms have been implicated depending on the etiology. Viral infections are an extremely rare cause, with only one case reported after an Epstein-Barr virus infection. In this case report, we have described the very likely association between SARS-CoV2 infection and the development of a time-limited acquired von Willebrand syndrome.

Human genetic and immunological determinants of SARS-CoV-2 and Epstein-Barr virus diseases in childhood: Insightful contrasts.

There is growing evidence to suggest that severe disease in children infected with common viruses that are typically benign in other children can result from inborn errors of immunity or their phenocopies. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a cytolytic respiratory RNA virus, can lead to acute hypoxemic COVID-19 pneumonia in children with inborn errors of type I interferon (IFN) immunity or autoantibodies against IFNs. These patients do not appear to be prone to severe disease during infection with Epstein-Barr virus (EBV), a leukocyte-tropic DNA virus that can establish latency. By contrast, various forms of severe EBV disease, ranging from acute hemophagocytosis to chronic or long-term illnesses, such as agammaglobulinemia and lymphoma, can manifest in children with inborn errors disrupting specific molecular bridges involved in the control of EBV-infected B cells by cytotoxic T cells. The patients with these disorders do not seem to be prone to severe COVID-19 pneumonia. These experiments of nature reveal surprising levels of redundancy of two different arms of immunity, with type I IFN being essential for host defense against SARS-CoV-2 in respiratory epithelial cells, and certain surface molecules on cytotoxic T cells essential for host defense against EBV in B lymphocytes.

Reactivation of herpesviruses during COVID-19: A systematic review and meta-analysis.

To provide a comprehensive systematic review and meta-analysis regarding the cumulative incidence (incidence proportion) of human herpesvirus (HHV) reactivation among patients with coronavirus disease 2019 (COVID-19), we searched PubMed/MEDLINE, Web of Science, and EMBASE up to 25 September 2022, with no language restrictions. All interventional and observational studies enrolling patients with confirmed COVID-19 and providing data regarding HHV reactivation were included. The random-effects model was used in the meta-analyses. We included information from 32 studies. HHV reactivation was considered a positive polymerase chain reaction result taken at the time of COVID-19 infection. Most of the included patients were severe COVID-19 cases. The pooled cumulative incidence estimate was 38% (95% Confidence Intervals [CI], 28%-50%, I2  = 86%) for herpes simplex virus (HSV), 19% (95% CI, 13%-28%, I2  = 87%) for cytomegalovirus (CMV), 45% (95% CI, 28%-63%, I2  = 96%) for Epstein-Barr virus (EBV), 18% (95% CI, 8%-35%) for human herpesvirus 6 (HHV-6), 44% (95% CI, 32%-56%) for human herpesvirus 7 (HHV-7), and 19% (95% CI, 14%-26%) for human herpesvirus 8 (HHV-8). There was no evidence of funnel plot asymmetry based on visual inspection and Egger's regression test for the results of HSV (p = 0.84), CMV (p = 0.82), and EBV (p = 0.27) reactivation. In conclusion, the identification of HHV reactivation in severe COVID-19 patients is helpful in the management of patients as well as the prevention of complications. Further research is required to elucidate the interaction between HHVs and COVID-19. Systematic review registration: PROSPERO CRD42022321973.

Long non-coding RNAs in virus-related cancers.

Some viral infections lead to tumourigenesis explained by a variety of underlying molecular mechanisms. Long non-coding RNAs (lncRNAs) have the potential to be added to this list due to their diverse mechanisms in biological functions and disease processes via gene alternation, transcriptional regulation, protein modification, microRNA sponging and interaction with RNA/DNA/proteins. In this review, we summarise the dysregulation and mechanism of lncRNAs in virus-related cancers focussing on Hepatitis B virus, Epstein-Barr virus, Human Papillomavirus. We will also discuss the potential implications of lncRNAs in COVID-19.

Comprehensive Investigations Relationship Between Viral Infections and Multiple Sclerosis Pathogenesis.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS). Compared to other types of self-limiting myelin disorders, MS compartmentalizes and maintains chronic inflammation in the CNS. Even though the exact cause of MS is unclear, it is assumed that genetic and environmental factors play an important role in susceptibility to this disease. The progression of MS is triggered by certain environmental factors, such as viral infections. The most important viruses that affect MS are Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), human endogenous retrovirus (HERV), cytomegalovirus (CMV), and varicella zoster virus (VZV). These viruses all have latent stages that allow them to escape immune detection and reactivate after exposure to various stimuli. Furthermore, their tropism for CNS and immune system cells explains their possible deleterious function in neuroinflammation. In this study, the effect of viral infections on MS disease focuses on the details of viruses that can change the risk of the disease. Paying attention to the most recent articles on the role of SARS-CoV-2 in MS disease, laboratory indicators show the interaction of the immune system with the virus. Also, strategies to prevent viruses that play a role in triggering MS are discussed, such as EBV, which is one of the most important.

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID.

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein-Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.

Epstein Barr Virus Reactivation during COVID-19 Hospitalization Significantly Increased Mortality/Death in SARS-CoV-2(+)/EBV(+) than SARS-CoV-2(+)/EBV(-) Patients: A Comparative Meta-Analysis.

Epstein-Barr virus (EBV) reactivation in acute-phase of COVID-19 disease was recently discovered but it is not clear in terms of degree of mortality caused, and this was the aim of the current study. Six databases and three non-databases were thoroughly searched, independently. The articles related to non-human study (abstract, in vitro, in vivo, in silico, case study, poster, and review articles) were excluded for main analysis. Four articles related to mortality linked to EBV reactivation were systematically identified and included in the qualitative and quantitative analyses. Based on proportional meta-analysis of 4 studies, 34.3% or 0.343 (95% CI: 0.189-0.516; I 2 = 74.6) mortality related to EBV reactivation was identified. To address high heterogeneity, subgroup meta-analysis was carried out. Based on subgroup analysis, 26.6% or 0.266 (95% CI: 0.191-0.348; I 2 = 0) with no heterogeneity was identified. Interestingly, in comparative meta-analysis, EBV(-)/SARS-CoV-2(+) patients had statistically lesser mortality (9.9%) than EBV(+)/SARS-CoV-2(+) patients (23.6%) where RR = 2.31 (95% CI: 1.34-3.99; p = 0.003; I 2 = 6%). This finding is equivalent to the absolute mortality effect of 130 more per 1000 COVID-19 patients (95% CI: 34-296). Furthermore, based on statistical analysis, D-dimer was not statistically significantly different (p > 0.05) between the groups although studies have shown that D-dimer was statistically significantly different (p < 0.05) between these groups. Based on the inclusion and analysis of low risk of bias and high quality of articles graded with Newcastle-Ottawa Scale (NOS), when COVID-19 patients' health state is gradually worsening, EBV reactivation needs to be suspected because EBV reactivation is a possible marker for COVID-19 disease severity.

Kikuchi-Fujimoto-like lymphadenopathy following COVID-19 vaccine: diagnosis and management.

A woman in her mid 40s presented for breast imaging after 1 week of painful and enlarged right axillary lymphadenopathy. She denied history of fever, weight loss, night sweats fatigue, cat scratch or other trauma. She received the second dose of Pfizer COVID-19 vaccine 3 months previously on the contralateral arm. A mammogram demonstrated a single, asymmetric, large and dense right axillary lymph node. Ultrasound confirmed a 2.5 cm lymph node with cortical thickening of 0.6 cm. Ultrasound-guided core biopsy showed necrotising lymphadenitis with associated aggregates of histiocytes and plasmacytoid dendritic cells. Potential causes of necrotising adenitis including Bartonella, tuberculosis, Epstein-Barr Virus, herpes simplex virus, systemic lupus erythematosus and lymphoma were excluded. In the absence of any identifiable infectious or autoimmune causes, and given the temporal relatedness with vaccine administration, it was determined that the Kikuchi-Fujimoto-like necrotising lymphadenitis was likely secondary to the COVID-19 vaccine. To date, there has been no casual association made between the COVID-19 vaccine and KFD necrotising lymphadenitis.

Case report: Cellular therapy for hydroa vacciniforme-like lymphoproliferative disorder in pediatric common variable immunodeficiency with chronic active Epstein-Barr virus infection.

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a cutaneous form of chronic active Epstein-Barrvirus (EBV) infection, which can develop into the extremely rare systemic lymphoma. Patients with Inborn errors of immunity (IEI), such as common variable immunodeficiency (CVID), are at higher risk of developing a severe course of infections especially viral and malignancies than the general population. The aim of the study was to present complex diagnostic and therapeutic management of HV-LPD. The clinical diagnosis was confirmed at the histological and molecular level with next generation sequencing. HV-LPD was diagnosed in a patient with CVID and chronic active Epstein-Barr virus (CAEBV) infection. The patient was refractory to CHOP chemotherapy and immunosuppressive treatment in combination with antiviral drugs (prednisone, bortezomib, gancyclovir). The third-party donor EBV-specific cytotoxic T cells (EBV-CTL, tabelecleucel) were used, which stabilised the disease course. Finally, matched unrelated donor hematopoietic cell transplantation (MUD-HCT) was performed followed by another cycle of EBV-CTL.

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.

Case of reactive sacroiliitis possibly induced by an mRNA coronavirus disease vaccine.

A woman in her 30s received a second dose, first booster, Corminaty vaccine against the SARS-CoV-2. Three days later, the patient developed unilateral sacroiliitis. A pelvic scan revealed inflammatory joint edges, bone erosion and a heterogeneous mass of 2.5 cm in the psoas muscle. Joint puncture revealed no microcrystalline deposits, but bone marrow cells, erythroblast were identified. The standard bacterial cultures and culture for mycobacteria were negative. HLA B27 was negative, and no seroconversion was identified for HIV, Epstein-Barr virus, cytomegalovirus, chlamydia or Quantiferon. Two months later, the sacroiliitis resolved.The aetiologic approach of this erosive unilateral acute sacroiliitis in a person naïve to rheumatologic pathology was negative for inflammatory or infectious sacroiliitis. Arthralgias after vaccination are expected. Arthritis is less common, and acute sacroiliitis has not yet been described. Acute sacroiliitis may be considered a reactive sacroiliitis to the anti-COVID-19 mRNA vaccine.