Enterovirus Infections in Solid Organ Transplant Recipients: a Clinical Comparison from a Regional University Hospital in the Netherlands.

Enterovirus infections are known to cause a diverse range of illnesses, even in healthy individuals. However, information detailing enterovirus infections and their severity in immunocompromised patients, such as transplant recipients, is limited. We compared enterovirus infections in terms of genotypes, clinical presentation, and severity between transplant and nontransplant patients. A total of 264 patients (38 transplant recipients) with 283 enterovirus infection episodes were identified in our hospital between 2014 and 2018. We explored the following factors associated with enterovirus infections: clinical presentation and diagnosis on discharge, length of hospital stay, symptom persistence, and infection episodes in both children and adults. We observed some differences in genotypes between patients, with enterovirus group C occurring mainly in transplant recipients (P < 0.05). EV-associated gastrointestinal infections were more common in patients with a transplant (children [71%] and adults [46%]), compared to nontransplant patients (P < 0.05). Additionally, nontransplant patients had a higher number of hospital stays (P < 0.05), potentially reflecting more severe disease. However, transplant patients were more likely to have symptom persistence after discharge (P < 0.05). Finally, children and adults with a transplant were more likely to have additional enterovirus infection episodes (P < 0.05). In our cohort, enterovirus infections did not seem to be more severe after transplantation; however, patients tended to present with different clinical symptoms and had genotypes rarely found in nontransplant recipients. IMPORTANCE Despite the high prevalence of enteroviruses in the community and the increasing demand for transplants from an aging population, knowledge on enteroviruses in solid organ transplant recipients is currently limited. Transplant recipients represent a significant patient population and require additional considerations in patient management, particularly as they have an increased risk of disease severity. Enteroviruses are known to cause significant morbidity, with a diverse range of clinical presentation from over 100 different genotypes. In this study, we aimed to provide a more comprehensive overview of enteroviral infections in transplant recipients, compared to nontransplant patients, and to bridge some gaps in our current knowledge. Identifying potential clinical manifestation patterns can help improve patient management following enterovirus infections.

Analysis of enterovirus genotypes in the cerebrospinal fluid of children associated with aseptic meningitis in Liaocheng, China, from 2018 to 2019.

BACKGROUND: Aseptic meningitis is most often caused by enteroviruses (EVs), but EVs associated with aseptic meningitis have not yet been reported in Liaocheng. The aim of this study was to determine the prevalence and genetic characteristics of EVs causing aseptic meningitis in children in Liaocheng. METHODS: We reviewed the epidemiological and clinical characteristics of 504 paediatric cases of aseptic meningitis in Liaocheng from 2018 to 2019 and analysed the phylogeny of the predominant EV types causing this disease. RESULTS: A total of 107 children were positive for EV in cerebrospinal fluid samples by nested PCR. Most of the positive patients were children 13 years old or younger and had symptoms such as fever, headache and vomiting (P < 0.05). The seasons with the highest prevalence of EV-positive cases were summer and autumn. The 107 EV sequences belonged to 8 serotypes, and echovirus types 18, 6 and 11 were the three dominant serotypes in Liaocheng during the 2-year study period. Phylogenetic analyses demonstrated that the E18 and E6 isolates belonged to subgenotype C2, while the E11 isolates belonged to subgenotype D5. VP1 analysis suggested that only one lineage of these three types was cocirculating in the Liaocheng region. CONCLUSIONS: This study demonstrated the diverse EV genotypes contributing to a large outbreak of aseptic meningitis in Liaocheng. Therefore, large-scale surveillance is required to assess the epidemiology of EVs associated with aseptic meningitis and is important for the diagnosis and treatment of aseptic meningitis in Liaocheng.

Selenium in Endocrinology-Selenoprotein-Related Diseases, Population Studies, and Epidemiological Evidence.

Selenium (Se), apart from iodine, iron, and calcium, is one of the nutrient-derived key elements strongly affecting the endocrine system. However, no specific hormonal "feedback" regulation for Se status has yet been identified, in contrast to the fine-tuned hormone network regulating Ca2+ and phosphate balance or hepcidin-related iron status. Since its discovery as an essential trace element, the effects of Se excess or deficiency on the endocrine system or components of the hypothalamic-pituitary-periphery feedback circuits, the thyroid hormone axis, glucoregulatory and adrenal hormones, male and female gonads, the musculoskeletal apparatus, and skin have been identified. Analysis of the Se status in the blood or via validated biomarkers such as the hepatically derived selenoprotein P provides valuable diagnostic insight and a rational basis for decision making on required therapeutic or preventive supplementation of risk groups or patients. Endocrine-related epidemiological and interventional evidence linking Se status to beneficial or potentially adverse actions of selected selenoproteins mediating most of the (patho-) physiological effects are discussed in this mini-review. Autoimmune thyroid disease, diabetes and obesity, male fertility, as well as osteoporosis are examples for which observational or interventional studies have indicated Se effects. The currently prevailing concept relating Se and selenoproteins to "oxidative stress," reactive oxygen species, radical hypotheses, and related strategies of pharmacological approaches based on various selenium compounds will not be the focus. The crucial biological function of several selenoproteins in cellular redox-regulation and specific enzyme reactions in endocrine pathways will be addressed and put in clinical perspective.

Clinical, etiological and epidemiological investigations of hand, foot and mouth disease in southern Vietnam during 2015 - 2018.

Hand, foot and mouth disease (HFMD) continues to challenge Asia with pandemic potential. In Vietnam, there have been two major outbreaks occurring during 2011-2012 (>200,000 hospitalizations and >200 deaths) and more recently in 2018 (>130,000 hospitalizations and 17 deaths). Given the high burden and the complex epidemic dynamics of HFMD, synthesizing its clinical and epidemiological data remains essential to inform the development of appropriate interventions and design public health measures. We report the results of a hospital-based study conducted during 2015-2018, covering the severe HFMD outbreak recently documented in Vietnam in 2018. The study was conducted at three major hospitals responsible for receiving HFMD patients from southern Vietnam with a population of over 40 million. A total of 19 enterovirus serotypes were detected in 1196 HFMD patients enrolled in the clinical study during 2015-2018, with enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6), CV-A10 and CV-A16 being the major causes. Despite the emergence of coxsackieviruses, EV-A71 remains the leading cause of severe HFMD in Vietnam. EV-A71 was consistently detected at a higher frequency during the second half of the years. The emergence of EV-A71 subgenogroup C4 in late 2018 was preceded by its low activity during 2017-early 2018. Compared with EV-A71 subgenogroup B5, C4 was more likely to be associated with severe HFMD, representing the first report demonstrating the difference in clinical severity between subgenogroup C4 and B5, the two predominant EV-A71 subgenogroups causing HFMD worldwide. Our data have provided significant insights into important aspects of HFMD over four years (2015-2018) in Vietnam, and emphasize active surveillance for pathogen circulation remains essential to inform the local public health authorities in the development of appropriate intervention strategies to reduce the burden of this emerging infections. Multivalent vaccines are urgently needed to control HFMD.

Rac1-dependent endocytosis and Rab5-dependent intracellular trafficking are required by Enterovirus A71 and Coxsackievirus A10 to establish infections.

Enterovirus A71 (EVA71) and Coxsackievirus A10 (CVA10) are representative types of Enterovirus A. Dependent on the host cell types, the EVA71 entry may utilize clathrin-, caveola-, and endophilin-A2-mediated endocytosis. However, the cell-entry and intracellular trafficking pathways of CVA10, using KREMEN1 as its receptor, are unclear. Here, we tested the relevant mechanisms through RNA interference (RNAi) and chemical inhibitors. We found that endocytosis of EVA71 and CVA10 in rhabdomyosarcoma (RD) cells engaged multiple pathways, and both viruses required Rac1. Interestingly, while CDC42 and Pak1 participated in EVA71 infection, PI3K played a role in CVA10 infection. The functions of Rab proteins in intracellular trafficking of CVA10 and EVA71 were examined by RNAi. Knockdown of Rab5 and Rab21 significantly reduced CVA10 infectivity, while knockdown of Rab5, Rab7 and Rab9 reduced EVA71 infectivity. Confocal microscopy confirmed the colocalization of CVA10 virions with Rab5 or Rab21, and colocalization of EVA71 virions with Rab5 or Rab7. Additionally, we observed that both CVA10 and EVA71 infections were inhibited by endosome acidification inhibitors, bafilomycin-A1 and NH4Cl. Together, our findings comparatively illustrate the entry and intracellular trafficking processes of representative Enterovirus A types and revealed novel enterovirus intervention targets.

Villitis of unknown etiology and chronic deciduitis are not associated with human papilloma virus and enterovirus infection.

Villitis of unknown etiology (VUE) and chronic deciduitis with plasma cells (CD) are supposed to be non infectious placental lesions caused by a pathologic immune reaction similar to a host versus graft mechanism. In some investigations, infection of human trophoblastic cells with human papilloma virus (HPV) has been described, and a relationship with miscarriage, preeclampsia, and chronic inflammatory placental lesions has been suspected. Infection with enterovirus, especially Coxsackievirus, has been observed in cases with spontaneous abortion and adverse perinatal outcome, respectively. We investigated 20 cases with VUE and 30 cases with chronic deciduitis with plasma cells. The placenta specimens were analyzed for expression of HPV capsid protein by immunohistochemistry, for presence of HPV DNA via polymerase chain reaction (PCR), and for presence of enterovirus mRNA using RT-PCR, respectively. VUE was associated with maternal diseases: atopic lesions in 21%, other autoimmune diseases in 15.5%, and obesity in 31.5%, respectively. Birth weight below the 10th percentile was detected in 63% of the cases with VUE. Chronic deciduitis was associated with preterm labor and preterm premature rupture of membranes (26%). Intrauterine fetal demise occurred in 5 cases with CD (18.5%). HPV DNA, HPV capsid protein, and enterovirus mRNA were not detected in all investigated VUE or CD cases. Our investigations show that a causal role for enterovirus and human papilloma virus in the development of VUE and CD is unlikely. Therefore, HPV vaccination is unlikely to reduce the incidence of VUE and CD in the future.

Enterovirus D68 in a 6-year-old acute flaccid myelitis case in China, 2018: a case report.

BACKGROUND: Acute flaccid myelitis (AFM) are reported to be associated with enterovirus D68 infection. Though an increasing number of AFM cases were reported with EV-D68 infection in the US, few such cases have been found in China. CASE PRESENTATION: A 6-year-old boy presented with acute flaccid myelitis (AFM) involving left arm after fever and respiratory symptoms for 6 days. Computed Tomography (CT) revealed inflammation in both lungs and magnetic resonance imaging (MRI) of the brain and spine showed swelling in the left frontal lobe and brain stem. The patient was diagnosed with meningomyelitis. EV-D68 was detected from pharyngeal samples 36 days after the onset of the disease. CONCLUSION: We report the first EV-D68 infection in case of AFM in mainland China. AFM surveillance systems is recommended to be established in China to guide diagnosis, case reporting, and specimen collection and testing for better understanding its etiologies.

Feline Virome-A Review of Novel Enteric Viruses Detected in Cats.

Recent advances in the diagnostic and metagenomic investigations of the feline enteric environment have allowed the identification of several novel viruses that have been associated with gastroenteritis in cats. In the last few years, noroviruses, kobuviruses, and novel parvoviruses have been repetitively detected in diarrheic cats as alone or in mixed infections with other pathogens, raising a number of questions, with particular regards to their pathogenic attitude and clinical impact. In the present article, the current available literature on novel potential feline enteric viruses is reviewed, providing a meaningful update on the etiology, epidemiologic, pathogenetic, clinical, and diagnostic aspects of the infections caused by these pathogens.

Fatal disseminated enterovirus infection in a patient with follicular lymphoma undergoing obinutuzumab maintenance therapy.

Follicular lymphoma is the most common subtype of the indolent non-Hodgkin lymphomas. Treatment usually consists of immuno-chemotherapy and results in long-lasting remissions in most cases. Progression-free survival with the second-generation anti-CD20 antibody obinutuzumab was shown to be better than with rituximab when given in combination with either bendamustine or anthracycline-based chemotherapy. Although treatment is generally well tolerated without an excessive rate of toxicities, there appear to be slightly more adverse events with obinutuzumab than with rituximab. Here, we report the case of a 45-year-old female patient that was diagnosed with a disseminated enterovirus infection while undergoing maintenance therapy with obinutuzumab after induction treatment with the combination of bendamustine and rituximab. Enterovirus RNA was detected in the blood, the cerebrospinal fluid, and the colon. A therapy with intravenous immunoglobulins was initiated since the patient presented with a severe treatment-related immunosuppression indicated by hypogammaglobulinemia. Nonetheless, she eventually died from the enterovirus infection without evidence of lymphoma progression. This case underscores that clinicians should be aware of rare but potentially fatal infectious complications related to treatment protocols containing anti-CD20 antibodies.

The aetiologies of central nervous system infections in hospitalised Cambodian children.

BACKGROUND: Central nervous system (CNS) infections are an important cause of childhood morbidity and mortality. The aetiologies of these potentially vaccine-preventable infections have not been well established in Cambodia. METHODS: We did a one year prospective study of children hospitalised with suspected CNS infection at Angkor Hospital for Children, Siem Reap. Cerebrospinal fluid specimens (CSF) samples underwent culture, multiplex PCR and serological analysis to identify a range of bacterial and viral pathogens. Viral metagenomics was performed on a subset of pathogen negative specimens. RESULTS: Between 1st October 2014 and 30th September 2015, 284 analysable patients were enrolled. The median patient age was 2.6 years; 62.0% were aged <5 years. CSF white blood cell count was ≥10 cells/µL in 116/272 (42.6%) cases. CNS infection was microbiologically confirmed in 55 children (19.3%). Enteroviruses (21/55), Japanese encephalitis virus (17/55), and Streptococcus pneumoniae (7/55) accounted for 45 (81.8%) of all pathogens identified. Of the pathogens detected, 74.5% (41/55) were viruses and 23.6% (13/55) were bacteria. The majority of patients were treated with ceftriaxone empirically. The case fatality rate was 2.5%. CONCLUSIONS: Enteroviruses, JEV and S. pneumoniae are the most frequently detected causes of CNS infection in hospitalised Cambodian children.

Enterovirus D68-Associated Acute Flaccid Myelitis in Immunocompromised Woman, Italy.

In Italy in 2016, acute flaccid myelitis developed in a woman who had received a hematopoietic stem cell transplant. Enterovirus D68 viral genome was detected in respiratory and cerebrospinal fluid samples, and the viral protein 1 sequence clustered with lineage B3. Immunocompromised adults may be at risk for enterovirus D68-associated neurologic complications.

Health risk assessment of environmental selenium: Emerging evidence and challenges (Review).

New data have been accumulated in the scientific literature in recent years which allow a more adequate risk assessment of selenium with reference to human health. This new evidence comes from environmental studies, carried out in populations characterized by abnormally high or low selenium intakes, and from high-quality and large randomized controlled trials with selenium recently carried out in the US and in other countries. These trials have consistently shown no beneficial effect on cancer and cardiovascular risk, and have yielded indications of unexpected toxic effects of selenium exposure. Overall, these studies indicate that the minimal amount of environmental selenium which is source of risk to human health is much lower than anticipated on the basis of older studies, since toxic effects were shown at levels of intake as low as around 260 µg/day for organic selenium and around 16 µg/day for inorganic selenium. Conversely, populations with average selenium intake of less than 13-19 µg/day appear to be at risk of a severe cardiomyopathy, Keshan disease. Overall, there is the need to reconsider the selenium standards for dietary intake, drinking water, outdoor and indoor air levels, taking into account the recently discovered adverse health effects of low-dose selenium overexposure, and carefully assessing the significance of selenium-induced proteomic changes.

Enteroviral infection in patients treated with rituximab for non-Hodgkin lymphoma: a case series and review of the literature.

In recent years, anti-CD20 antibodies have been increasingly used to treat lymphoproliferative and immune disorders. Chronic viral infections are infrequently reported in patients receiving these therapies. Enteroviral infection can cause life-threatening meningoencephalitis and other systemic chronic syndromes in immune deficient patients. We describe the clinical courses and outcomes of 6 patients from 2 tertiary care institutions who developed chronic enteroviral infection with neurological manifestations, after combined chemoimmunotherapy with rituximab for B-cell lymphoma. We review the literature that includes 10 sporadic reported cases of chronic enteroviral meningoencephalitis attributed to rituximab therapy. It is a rare disease, and its diagnosis is often elusive. We propose that low immunoglobulin G levels are the main risk factor for developing chronic enteroviral infection and emphasize the need for a high index of suspicion, early diagnosis, and intervention in this iatrogenic and potentially fatal complication.

Changes in enterovirus serotype constituent ratios altered the clinical features of infected children in Guangdong Province, China, from 2010 to 2013.

BACKGROUND: Enterovirus (EV)-related hand, foot, and mouth disease/herpangina (HFMD/HA) has been prevalent in Guangdong Province, China, since 2010. METHODS: Clinical data for EV-related HFMD/HA inpatients admitted to the Department of Paediatrics of Zhujiang Hospital from 2010 to 2013 were retrospectively reviewed. The corresponding EV serotypes were also determined by reverse transcription-polymerase chain reaction or BLAST analysis of the sequenced partial lengths of the viral protein1/5'-untranslated region. RESULTS: A total of 867 eligible inpatients admitted during 2010-2013 were included in the study. Of these, the serotype of the responsible EV was successfully identified in 824 cases. The incidence of enterovirus 71 (EV71) infection amongst pediatric HFMD/HA inpatients decreased dramatically from 55.5 % in 2010 to 8.1 % in 2013, with a similar decrease recorded for coxsackievirus A16 (CVA16). However, the incidence of non-EV71/CVA16 infection increased from 30.0 % in 2010 to 83.8 % in 2013. We noted that the types of infection caused by different EV serotypes varied: EV71 was responsible for 100 % of the paralysis cases (26/26), 84.6 % of the deaths (11/13), and 84.1 % of cases with severe central nervous system involvement (SCNSI) (74/88); echovirus contributed to 16.4 % of the deaths (2/13) and 4.4 % of the SCNSI cases; and coxsackievirus accounted for only 2.2 % of the SCNSI cases (2/90). The clinical features of HFMD/HA cases varied greatly during the time period examined, with drastic changes in the hospitalization rates (45.1, 63.7, 36.4, and 19.1 % for 2010, 2011, 2012, and 21013, respectively), mortality rates (2.3, 0.9, 2.5, and 0.0 %, respectively), paralysis (5.1, 1.2, 5.4, and 0.0 %, respectively), SCNSI (16.8, 7.1, 12.7, and 2.2 %, respectively), and acute respiratory infection (21.1, 22.0, 45.9, and 59.0 %, respectively). CONCLUSIONS: The incidences of infection caused by different EV serotypes, along with the clinical features of HFMD/HA cases, changed drastically in Guangdong Province, China, from 2010 to 2013, with the biggest changes observed in 2013. The changed constituent ratios of the different EV serotypes might therefore be responsible for the differences in the observed clinical features of HFMD/HA during this period.

[Expression and significance of toll-like receptors 7 and 8 in brain and lung tissues of death cases caused by EV71 infection].

OBJECTIVE: To study the significance of toll-like receptors (TLR) -7 and -8 in the pathogenesis of infection caused by Enterovirus type 71 (EV71) through measuring the expression of TLR7 and TLR8 in brain and lung tissues from the death cases caused by EV71 infection. METHODS: Nine children who died of EV71 infection (EV71 group) were selected as study subjects, and 7 children who died of accidents or non-infectious diseases were used as the control group. Brain and lung tissues from the death cases in both groups at autopsy were collected, and immunohistochemistry was applied to detect the expression of TLR7 and TLR8 in lung and brain tissues in both groups. Integrated optical density (IOD) was applied for semi-quantitative analysis of the expression of TLR7 and TLR8. RESULTS: Immunohistochemical results showed that the expression of TLR7 and TLR8 in lung and brain tissues was strongly positive in the EV71 group, and the IOD values in the EV71 group were also significantly higher than those in the control group (P<0.05). There was no significant difference in the expression of TLR7 and TLR8 between lung and brain tissues in the EV71 group (P>0.05). CONCLUSIONS: TLR7 and TLR8 are highly expressed in lung and brain tissues from the patients who die of severe EV71 infection, suggesting that TLR7 and TLR8 may be involved in the pathogenesis of brain and lung damages caused by severe EV71 infection.

Disseminated Enteroviral Infection Associated with Obinutuzumab.

Two cases of disseminated enteroviral infection occurred in patients who received the CD20 monoclonal antibody obinutuzumab. Clinical features included hepatitis, edema, and a dermatomyositis-like syndrome. These manifestations may be unfamiliar to clinicians and are possibly responsive to intravenous immunoglobulin. Clinicians should remain vigilant for enteroviral infections in patients receiving obinutuzumab.