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Enterovirus A71 (EV-A71) is the main pathogen causing hand, foot and mouth disease (HFMD) in children and occasionally associated with neurological diseases such as aseptic meningitis, brainstem encephalitis (BE) and acute flaccid paralysis. We report here that cellular pseudokinase tribbles 3 (TRIB3) facilitates the infection of EV-A71 via dual mechanisms. In one hand, TRIB3 maintains the metabolic stability of scavenger receptor class B member 2 (SCARB2), the bona fide receptor of EV-A71, to enhance the infectious entry and spreading of the virus. On the other hand, TRIB3 facilitates the replication of EV-A71 RNA in a SCARB2-independent manner. The critical role of TRIB3 in EV-A71 infection and pathogenesis was further demonstrated in vivo in mice. In comparison to wild-type C57BL/6 mice, EV-A71 infection in TRIB3 knockdown mice ( Trib3 +/- ) resulted in significantly lower viral loads in muscular tissues and reduced lethality and severity of clinical scores and tissue pathology. In addition, TRIB3 also promoted the replication of coxsackievirus B3 (CVB3) and coxsackievirus A16 (CVA16) in vitro . In conclusion, our results suggest that TRIB3 is one of key host cellular proteins required for the infection and pathogenesis of EV-A71 and some other human enteroviruses and may thus be a potential therapeutic target for combating the infection of those viruses.

Background and Objectives : the principal purpose of this literature review is to cluster adults with hematological malignancies after treatment or on maintenance with obinutuzumab who experienced disseminated EV infection to understand clinical characteristics and outcome of this rare condition in these patients. We report the first clinical case of a male affected by follicular lymphoma treated with immune-chemotherapy including obinutuzumab who was affected by disseminated EV infection with cardiovascular involvement. Materials and Methods : this narrative review summarizes all the research about disseminated EV infection in immunosuppressed adult patients treated with obinutuzumab from January 2000 to January 2024 using the Scale for the Assessment of Narrative Review Articles (SANRA) flow-chart. We performed a descriptive statistic using the standard statistical measures for quantitative data. Results : we included six studies, five case reports, and one case report with literature analysis. We collected a total of seven patients, all female, with disseminated EV infection. The most common signs and clinical presentations of EV infection were fever and encephalitis symptoms (N = 6, 85.7%), followed by hepatitis/acute liver failure (N = 5, 71.4%). Conclusions : onco-hematological patients who receive immune-chemotherapy with a combination of treatments which depress adaptative immunity, which includes the antiCD20 obinutuzumab, could be at higher risk of disseminated EV infection, including CNS and cardiac involvement.

Rationale: Hand-foot-mouth disease (HFMD) caused by Enterovirus A71, complicated by cardiopulmonary failure, is associated with a high mortality rate despite intensive treatment. To date, there is a paucity of clinical management data, regarding the use of extracorporeal life support (VA-ECMO) for Enterovirus-A71 associated cardiopulmonary failure reported., Patient Concerns: The patient in this study presented with severe HFMD complicated by cardiopulmonary failure, polymorphic ventricular tachycardia, and cardiac arrest., Diagnoses: Clinical presentations, laboratory data, and polymerase chain reaction (PCR) results from rectal swabs were used to confirm the diagnosis of severe HFMD caused by Enterovirus A71., Interventions: The patient was managed with chest compression and an automatic external defibrillator, mechanical ventilation, intravenous immunoglobulin (IVIG), continuous renal replacement therapy (CRRT) and inotrope (milrinone). The patient did not respond to these interventions and subsequently required further management with VA-ECMO., Outcomes: The patient achieved a favorable outcomes., Lessons: Our study highlights that extracorporeal membrane oxygenation and CRRT can enhance the survival outcomes of patients with severe HFMD with cardiopulmonary failure complications. Furthermore, we propose specific indications for the initiation of VA-ECMO., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Keshan disease (KD) is a type of endemic cardiomyopathy with an unknown cause. It is primarily found in areas in China with low selenium levels, from northeast to southwest. The nutritional biogeochemical etiology hypothesis suggests that selenium deficiency is a major factor in KD development. Selenium is important in removing free radicals and protecting cells and tissues from peroxide-induced damage. Thus, low environmental selenium may affect the selenium level within the human body, and selenium level differences are commonly observed between healthy people in KD and nonKD areas. From the 1970s to the 1990s, China successfully reduced KD incidence in endemic KD areas through a selenium supplementation program. After years of implementing prevention and control measures, the selenium level of the population in the KD areas has gradually increased, and the prevalence of KD in China has remained low and stable in recent years. Currently, the pathogenesis of KD remains vague, and the effect of selenium supplementation on the prognosis of KD still needs further study. This paper comprehensively reviews selenium deficiency and its connection to KD. Thus, this study aims to offer novel ideas and directions to effectively prevent and treat KD in light of the current situation.

Introduction: For more than a century, enteroviral infections have been associated with autoimmunity and type 1 diabetes (T1D). Uncontrolled viral response pathways repeatedly presented during childhood highly correlate with autoimmunity and T1D. Virus responses evoke chemokines and cytokines, the "cytokine storm" circulating through the body and attack cells especially vulnerable to inflammatory destruction. Intra-islet inflammation is a major trigger of β-cell failure in both T1D and T2D. The genetic contribution of islet inflammation pathways is apparent in T1D, with several mutations in the interferon system. In contrast, in T2D, gene mutations are related to glucose homeostasis in β cells and insulin-target tissue and rarely within viral response pathways. Therefore, the current study evaluated whether enteroviral RNA can be found in the pancreas from organ donors with T2D and its association with disease progression., Methods: Pancreases from well-characterized 29 organ donors with T2D and 15 age- and BMI-matched controls were obtained from the network for pancreatic organ donors with diabetes and were analyzed in duplicates. Single-molecule fluorescence in-situ hybridization analyses were performed using three probe sets to detect positive-strand enteroviral RNA; pancreas sections were co-stained by classical immunostaining for insulin and CD45., Results: There was no difference in the presence or localization of enteroviral RNA in control nondiabetic and T2D pancreases; viral infiltration showed large heterogeneity in both groups ranging from 0 to 94 virus + cells scattered throughout the pancreas, most of them in the exocrine pancreas. Very rarely, a single virus + cell was found within islets or co-stained with CD45 + immune cells. Only one single T2D donor presented an exceptionally high number of viruses, similarly as seen previously in T1D, which correlated with a highly reduced number of β cells., Discussion: No association of enteroviral infection in the pancreas and T2D diabetes could be found. Despite great similarities in inflammatory markers in islets in T1D and T2D, long-term enteroviral infiltration is a distinct pathological feature of T1D-associated autoimmunity and in T1D pancreases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Geravandi, Grasso, Sikdar, Pugliese and Maedler.)

Enteroviruses are a common cause of seasonal childhood infections. The vast majority of enterovirus infections are mild and self-limiting, although neonates can sometimes develop severe disease. Myocarditis is a rare complication of enterovirus infection. Between June 2022 and April 2023, twenty cases of severe neonatal enteroviral myocarditis caused by coxsackie B viruses were reported in the United Kingdom. Sixteen required critical care support and two died. Enterovirus PCR on whole blood was the most sensitive diagnostic test. We describe the initial public health investigation into this cluster and aim to raise awareness among paediatricians, laboratories and public health specialists.

Background: Enterovirus A71 is one of the causative agents of hand, foot, and mouth disease, which is usually a self-limiting disease. Complications of enterovirus infection are also very rare. However, when such complications occur, they can lead to serious neurological diseases or even death., Case Presentation: In this report, we describe a case of enterovirus A71-associated acute flaccid paralysis in a 13-month-old Caucasian girl that was managed in our hospital. The patient presented with sudden onset of left arm paresis that could not be attributed to any other cause. Establishing a diagnosis was furthermore complicated by negative virological investigations of cerebrospinal fluid and non-pathological radiological findings. A polymerase chain reaction test of the child's stool sample however tested positive for enterovirus and sequencing results revealed the presence of enterovirus A71. A previous history of febrile gastroenteritis just before the paresis started also supported the suspected diagnosis of enterovirus-associated acute flaccid paralysis. Following this, the child was treated with intravenous immunoglobulin over 5 days and a remarkable improvement was observed in the child's paresis., Conclusion: This case report describes a possible complication of enterovirus A71 infection in a child. It also highlights the prolonged detection of enterovirus in the child's stool sample as compared with cerebrospinal fluid weeks after the primary infection occurred. Finally, it shows the need for increased clinical and diagnostic awareness especially in the management of sudden and unknown causes of paresis or paralysis in children., (© 2023. The Author(s).)

A decade-long neglect of rhinovirus as an important agent of disease in humans was primarily due to the fact that they were seen as less virulent and capable of causing only mild respiratory infections such as common cold. However, with an advent of molecular diagnostic methods, an increasing number of reports placed them among the pathogens found in the lower respiratory tract and recognized them as important risk factors for asthma-related pathology in childhood. As the spread of rhinovirus was not severely affected by the implementation of social distancing and other measures during the coronavirus disease 2019 (COVID-19) pandemic, its putative pathogenic role has become even more evident in recent years. By concentrating on children as the most vulnerable group, in this narrative review we first present classification and main traits of rhinovirus, followed by epidemiology and clinical presentation, risk factors for severe forms of the disease, long-term complications and the pathogenesis of asthma, as well as a snapshot of treatment trials and studies. Recent evidence suggests that the rhinovirus is a significant contributor to respiratory illness in both high-risk and low-risk populations of children.

Neurodegenerative diseases (NDs) are increasingly common, especially in populations with higher life expectancies. They are associated mainly with protein metabolism and structure changes, leading to neuronal cell death. Viral infections affect these cellular processes and may be involved in the etiology of several neurological illnesses, particularly NDs. Enteroviruses (EVs) frequently infect the central nervous system (CNS), causing neurological disease. Inflammation, disruption of the host autophagy machinery, and deregulation and accumulation/misfolding of proteins are the main alterations observed after infection by an EV. In this perspective, we discuss the most recent findings on the subject, examining the possible role of EVs in the development of NDs, and shedding light on the putative role played by these viruses in developing NDs.

Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual "diabetogenic" microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4 + T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Morse, Simister, Crowe, Horwitz and Osborne.)

Background & Objectives: Focus on non-polio enteroviruses (NPEVs) causing acute flaccid paralysis (AFP) due to myelitis has increased with the containment of the poliovirus. Enterovirus-B88 (EV-B88) has been associated with the AFP cases in Bangladesh, Ghana, South Africa, Thailand and India. In India, EV-B88 infection was linked to AFP a decade ago; however, to date, no complete genome has been made available. In this study, the complete genome sequence of EV-B88 was identified and reported from two different States (Bihar and Uttar Pradesh) in India using the next-generation sequencing technique., Methods: Virus isolation was performed on the three AFP suspected cases as per the WHO-recommended protocol. Samples showing cytopathic effects in the human Rhabdocarcinoma were labelled as NPEVs. Next-generation sequencing was performed on these NPEVs to identify the aetiological agent. The contiguous sequences (contigs) generated were identified, and reference-based mapping was performed., Results: EV-B88 sequences retrieved in our study were found to be 83 per cent similar to the EV-B88 isolate from Bangladesh in 2001 (strain: BAN01-10398; Accession number: AY843306.1). Recombination analyses of these samples demonstrate recombination events with sequences from echovirus-18 and echovirus-30., Interpretation & Conclusions: Recombination events in the EV-B serotypes are known, and this work reconfirms the same for EV-B88 isolates also. This study is a step in increasing the awareness about EV-B88 in India and emphasizes future studies to be conducted in the identification of other types of EV present in India.

While the aetiology of asthma is unclear, the onset and/or exacerbation of asthma may be associated with respiratory infections. Virus-induced asthma is also known as virus-associated/triggered asthma, and the reported main causative agent is rhinovirus (RV). Understanding the relationship between viral infections and asthma may overcome the gaps in deferential immunity between viral infections and allergies. Moreover, understanding the complicated cytokine networks involved in RV infection may be necessary. Therefore, the complexity of RV-induced asthma is not only owing to the response of airway and immune cells against viral infection, but also to allergic immune responses caused by the wide variety of cytokines produced by these cells. To better understand RV-induced asthma, it is necessary to elucidate the nature RV infections and the corresponding host defence mechanisms. In this review, we attempt to organise the complexity of RV-induced asthma to make it easily understandable for readers.

Background: CMV gastroenteritis is common in patients receiving allogeneic hematopoietic stem cell transplantation and it is difficult to distinguish from acute graft-versus-host disease (aGvHD), which has very similar symptoms but needs quite different treatment. CMV gastroenteritis is caused by local infection or reactivation of CMV in the gastrointestinal tract while aGvHD is due to immune rejection. The gold standard of diagnosis of CMV gastroenteritis and aGvHD is gastrointestinal biopsy under endoscopy, which is invasive and can potentially lead to severe side effects. Stool samples testing with quantitative polymerase chain reaction (qPCR) may be an alternative, while the application in trace level measurements and precision are not all satisfactory enough in reported research., Methods: In this study, we designed a novel method that extracted the cell free DNA (cfDNA) from the fecal supernatant to perform digital PCR (dPCR) for the detection of CMV, analyzed the performance and compared it with the total DNA extracted by the current procedure., Results: Twenty-two paired stool samples using two DNA extraction methods proved that the cfDNA extraction method had markedly higher DNA concentrations and control gene copy number, suggesting that cfDNA may be more informative and more useful for the detection of CMV DNA segment. The dPCR approach in detecting CMV DNA segment also exhibit good linearity (R 2  = 0.997) and higher sensitivity (limit of detection at 50% was 3.534 copies/μL). Eighty-two stool samples from 44 immunocompromised patients were analyzed, CMV-positive rate was 28%, indicating that more than one-quarter of the gastrointestinal symptoms within these patients may be caused by CMV infection or reactivation., Conclusion: The combined results suggest that detection of CMV by dPCR in cfDNA of stool supernatant is a powerful method to identify CMV gastroenteritis and helps in clinical treatment decision making., (© 2022. The Author(s).)

Rhinoviruses (RV) account for a significant number of asthma exacerbations, and RV species C may be associated with a severe course in vulnerable patient groups. Despite important evidence on the role of RV reported by clinicians and life scientists, there are still unanswered questions regarding their influence on asthma exacerbation in young patients. Thus, we measured the RVspecies-specific IgG titers in our German pediatric exacerbation cohort using a microarray-based technology. For this approach, human sera of patients with exacerbated asthma and wheeze, as well as healthy control subjects ( n = 136) were included, and correlation analyses were performed. Concordantly with previously published results, we observed significantly higher cumulative levels of RV species A-specific IgG ( p = 0.011) and RV-C-specific IgG ( p = 0.051) in exacerbated asthma group compared to age-matched controls. Moreover, atopic wheezers had increased RV-specific IgG levels for species A ( p = 0.0011) and species C ( p = 0.0009) compared to non-atopic wheezers. Hypothesizing that bacterial infection positively correlates with immune memory against RV, we included nasopharyngeal swab results in our analyses and detected limited correlations. Interestingly, the eosinophil blood titer positively correlated with RV-specific IgG levels. With these observations, we add important observations to the existing data regarding exacerbation in pediatric and adolescent medicine. We propose that scientists and clinicians should pay more attention to the relevance of RV species in susceptible pediatric patients.

Human enterovirus D68 (EV-D68) is a globally reemerging respiratory pathogen that is associated with the development of acute flaccid myelitis (AFM) in children. Currently, there are no approved vaccines or treatments for EV-D68 infection, and there is a paucity of data related to the virus and host-specific factors that predict disease severity and progression to the neurologic syndrome. EV-D68 infection of various animal models has served as an important platform for characterization and comparison of disease pathogenesis between historic and contemporary isolates. Still, there are significant gaps in our knowledge of EV-D68 pathogenesis that constrain the development and evaluation of targeted vaccines and antiviral therapies. Continued refinement and characterization of animal models that faithfully reproduce key elements of EV-D68 infection and disease is essential for ensuring public health preparedness for future EV-D68 outbreaks.

Acute flaccid myelitis (AFM) is a neuroinflammatory disease characterized by acute asymmetric weakness of the limbs associated with lesions of the gray matter of the spinal cord. It mainly affects children and has been increasingly identified since 2014., Objective: To describe a severe emerging neurological disease in Chile., Clinical Case: Three children (2 females), previously healthy were in cluded. The age at the onset was between 4 and 6 years. All presented an acute febrile illness associated with upper respiratory symptoms, rapid onset of proximal asymmetric limb weakness, spinal fluid pleocytosis, and enterovirus isolated from nasopharyngeal swab; two patients developed tetraparesis. The MRI of the spinal cord showed T2 hyperintensity of the grey matter. The three patients were admitted to the Pediatric Intensive Care Unit (PICU), and two required mechanical ventilation. No significant improvements were observed after the use of immunomodulatory therapy and plasma ex change. At 12 months of follow-up, one case was quadriplegic and ventilator-dependent; the second died of ventricular arrhythmia in the PICU, and the third one is under rehabilitation with partial recovery., Conclusions: We report the first cases of this severe emerging neurological disease in our country. In a child with predominantly proximal and asymmetric acute limb paralysis, pediatricians must have a high index of suspicion for AFM. Since it can progress rapidly and lead to respiratory failure, suspected AFM should be considered a medical emergency.

Introduction: Human rhinovirus is a major cause of acute respiratory infections (ARIs) worldwide. Epidemiological data on human rhinovirus (RV) in Peru is still scarce, as well as its role in respiratory infections in children. Therefore, the aim of this study was to describe the prevalence of rhinovirus and to identify the circulating species in nasopharyngeal swabs from children with acute respiratory infections., Materials and Methods: We analyzed nasopharyngeal swab samples that were collected from children younger than 17 years old, who had a clinical diagnosis of ARI from the "Hospital Nacional Cayetano Heredia" between May 2009 and December 2010. The original study recruited 767 inpatients with ARI, 559 samples of which were included and analyzed in the current study. Detection of rhinovirus and determination of rhinovirus species were characterized by PCR., Results: Rhinovirus was detected in 42.22% samples (236/559), RV-A was detected in 10.17% (24/236) of the cases, RV-B in 16.53% (39/236), and RV-C in 73.31% (173/236). The age group with the highest number of cases was the 0-5 months group with 45.97%, followed by the 1-5 years group with 25.22%. Most of the positive RV cases, i.e., 86.44% (204/236), were hospitalized. The most common signs and symptoms found in patients who tested positive for RV were cough (72.88%), fever (68.64%), rhinorrhea (68.22%), and respiratory distress (61.44%). Infection with RV-A was associated with wheezing (p = 0.02). Furthermore, RV-C was related to cough (p = 0.01), wheezing (p = 0.002), and conjunctival injection (p = 0.03). A peak in RV-C cases was found in March (32 cases in 2010); June (18 cases in 2009 and 12 cases in 2010), which corresponds to the fall season in Peru; and also November (17 cases in 2009 and 4 cases in 2010), which corresponds to spring. RV-A and RV-B cases were constant throughout the year., Conclusion: In conclusion, we found a high prevalence of rhinovirus C infection among pediatric patients with acute respiratory infections in Lima, Peru. This viral infection was more common in children between 0 to 5 months old, and was associated with cough, wheezing, and conjunctival injection. Epidemiological surveillance of this virus should be strengthened/encouraged in Peru to determine its real impact on respiratory infections., Competing Interests: The authors have declared that no competing interests exist.

Objective: This study aimed to test the hypothesis that fibromyalgia is associated with a human enteroviral infection., Methods: Venous peripheral blood samples from 27 patients fulfilling the American College of Rheumatology revised diagnostic criteria for fibromyalgia and from 26 age- and sex-matched controls, who underwent immunofluorescence assays for coxsackievirus A7 IgG, coxsackievirus B1 IgG, coxsackievirus A7 IgA, coxsackievirus B1 IgA, echovirus IgG, and echovirus IgA. These immunological tests were performed blind to group status., Results: There were no significant differences between the patient and control groups in respect of positive results for coxsackievirus A7 IgG (p=0.467), coxsackievirus B1 IgG (p=0.491), coxsackievirus A7 IgA (p=0.586), coxsackievirus B1 IgA (p=0.467), echovirus IgG (p=0.236), and echovirus IgA (p=1)., Conclusions: The results of this systematic study do not support the hypothesis that fibromyalgia is associated with infection by a human enterovirus.

Enterovirus 71 (EV71) is the main pathogenic virus that causes hand, foot, and mouth disease (HFMD). Studies have reported that EV71-induced infections including aseptic meningitis, acute flaccid paralysis, and even neurogenic pulmonary edema, can progress to severe neurological complications in infants, young children, and the immunosuppressed population. However, the mechanisms through which EV71 causes neurological diseases have not been fully explored. Non-coding RNAs (ncRNAs), are RNAs that do not code for proteins, play a key role in biological processes and disease development associated with EV71. In this review, we summarized recent advances concerning the impacts of ncRNAs on neurological diseases caused by interaction between EV71 and host, revealing the potential role of ncRNAs in pathogenesis, diagnosis and treatment of EV71-induced neurological complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Zhang, Chen, Yin, Xu, Cheng, Ma, Meng and Du.)

Background: Acute flaccid myelitis is a serious condition of the spinal cord. More than 80% of patients experience a mild respiratory illness or fever consistent with a viral infection prior to acute flaccid myelitis development. Enterovirus A71 is known to circulate in Denmark, and has previously been associated with severe neurological symptoms. In this case report we describe acute flaccid rhombencephalomyelitis with radiculitis in an infant with an enterovirus infection., Case Presentation: The 8-month-old male of Asian origin presented with fever and gastrointestinal symptoms, followed by severe neurological deficits such as flaccid paralysis of the neck and upper extremities. An initial magnetic resonance imaging scan of the brain was normal, and the boy was treated for encephalitis. A follow-up magnetic resonance imaging scan of the brain and spinal cord 1 week later showed the development of pathological symmetrical gray matter hyperintensity lesions on T2-weighted images in the brainstem and upper medulla spinalis, and nerve enhancement in the terminal thread of the spinal cord and the cervical roots; findings consistent with rhombencephalomyelitis with radiculitis causing flaccid paralysis. Enterovirus A71 was detected in both nasopharyngeal and fecal specimens. Other differential diagnostic etiologies of viral and bacterial encephalitis, including poliovirus, were excluded., Conclusions: This is the first case in Denmark of a patient diagnosed with acute flaccid rhombencephalomyelitis strongly linked to an enterovirus A71 infection. This case emphasizes the diagnostic importance of combining a history of respiratory and/or gastrointestinal illness, fever, and delayed onset of varying degrees of paralysis with progressive characteristic spinal and brain lesions. Analysis of respiratory, fecal, and cerebrospinal samples for the presence of enterovirus, and eliminating other differential pathogens, is essential to confirm the diagnosis., (© 2022. The Author(s).)

Background: Enterovirus has been described as a cause of aseptic meningitis in humorally immunosuppressed patients., Case Presentation: A 67-year-old female with a history of mantle cell lymphoma on rituximab therapy presented with subacute hepatitis, myalgias, and sensorineural hearing loss several months after an initial febrile illness. She was diagnosed with enterovirus infection by CSF PCR as a unifying etiology of her presentation, representing an unusual presentation of disease., Discussion and Conclusions: This patient's unique presentation and clinical course presents important implications in the care of similarly immunosuppressed patients with cryptic complaints., (© 2021. The Author(s).)

Numerous animal models and epidemiological and observational studies have demonstrated that enterovirus (EV) infection could be involved in the development of clinical type 1 diabetes mellitus (T1DM), but its aetiology is not fully understood. Therefore, we reviewed the association between EV infection and clinical T1DM. We searched PubMed and Embase from inception to April 2021 and reference lists of included studies without any language restrictions in only human studies. The correlation between EV infection and clinical T1DM was calculated as the pooled odds ratio (OR) and 95% confidence intervals (CIs), analysed using random-effects models. Subgroup and sensitivity analyses were performed to evaluate the robustness of the associations. A total of 25 articles (22 case-control studies and three nested case-control studies) met the inclusion criterion including 4854 participants (2948 cases and 1906 controls) with a high level of statistical heterogeneity (I2 = 80%, P < 0.001) mainly attributable to methods of EV detection, study type, age distribution, source of EV sample and control subjects. Meta-analysis showed a significant association between EV infection and clinical T1DM (OR 5.75, 95% CI 3.61-9.61). There is a clinically significant association between clinical T1DM and EV infection.

Introduction: Patients with hemoglobinopathies have been reported to have higher rates of pulmonary complications. Few studies have investigated the association between thalassemia and asthma in children., Methods: We used the data of one million individuals randomly selected from the Registry for Beneficiaries of the National Health Insurance Research Database. One thalassemic child was matched with four control children without thalassemia according to sex, birth year, birth season, prematurity, and previous enteroviral infection., Results: A total of 800 hundred thalassemic children and 3200 controls were included. Children with thalassemia had higher rates of developing asthma (41.81 vs 25.70 per 1000 person-years, P < 0.001) than the non-thalassemia controls with an adjusted hazard ratio of 1.37 (95% confidence interval [CI] = 1.19-1.58). Boys in the thalassemia cohort had a significantly higher adjusted incidence hazard ratio (IRR) of asthma than those in the non-thalassemia cohort (adjusted IRR = 1.45, 95% CI = 1.02-1.73). The risk of atopic and nonatopic asthma was higher in the thalassemia cohort than in the non-thalassemia cohort (IRR = 1.3, 1.61, respectively)., Conclusions: Children with thalassemia were more likely to develop asthma. More attention should be paid to the early diagnosis of asthma and prevention of asthma attacks., Competing Interests: The authors have declared that no competing interests exist.

Enterovirus A71 (EV-A71) and many members of the Picornaviridae family are neurotropic pathogens of global concern. These viruses are primarily transmitted through the fecal-oral route, and thus suitable animal models of oral infection are needed to investigate viral pathogenesis. An animal model of oral infection was developed using transgenic mice expressing human SCARB2 (hSCARB2 Tg), murine-adapted EV-A71/MP4 virus, and EV-A71/MP4 virus with an engineered nanoluciferase gene that allows imaging of viral replication and spread in infected mice. Next-generation sequencing of EV-A71 genomes in the tissues and organs of infected mice was also performed. Oral inoculation of EV-A71/MP4 or nanoluciferase-carrying MP4 virus stably induced neurological symptoms and death in infected 21-day-old weaned mice. In vivo bioluminescence imaging of infected mice and tissue immunostaining of viral antigens indicated that orally inoculated virus can spread to the central nervous system (CNS) and other tissues. Next-generating sequencing further identified diverse mutations in viral genomes that can potentially contribute to viral pathogenesis. This study presents an EV-A71 oral infection murine model that efficiently infects weaned mice and allows tracking of viral spread, features that can facilitate research into viral pathogenesis and neuroinvasion via the natural route of infection. IMPORTANCE Enterovirus A71 (EV-A71), a positive-strand RNA virus of the Picornaviridae , poses a persistent global public health problem. EV-A71 is primarily transmitted through the fecal-oral route, and thus suitable animal models of oral infection are needed to investigate viral pathogenesis. We present an animal model of EV-A71 infection that enables the natural route of oral infection in weaned and nonimmunocompromised 21-day-old hSCARB2 transgenic mice. Our results demonstrate that severe disease and death could be stably induced, and viral invasion of the CNS could be replicated in this model, similar to severe real-world EV-A71 infections. We also developed a nanoluciferase-containing EV-A71 virus that can be used with this animal model to track viral spread after oral infection in real time. Such a model offers several advantages over existing animal models and can facilitate future research into viral spread, tissue tropism, and viral pathogenesis, all pressing issues that remain unaddressed for EV-A71 infections.

Objective: The association between enterovirus infection and type 1 diabetes (T1D) is controversial, and this meta-analysis aimed to explore the correlation., Methods: PubMed, Embase, Web of Science, and Cochrane Database were searched from inception to April 2020. Studies were included if they could provide sufficient information to calculate odds ratios and 95% confidence intervals. All analyses were performed using STATA 15.1., Results: Thirty-eight studies, encompassing 5921 subjects (2841 T1D patients and 3080 controls), were included. The pooled analysis showed that enterovirus infection was associated with T1D ( P < 0.001). Enterovirus infection was correlated with T1D in the European ( P < 0.001), African ( P = 0.002), Asian ( P = 0.001), Australian ( P = 0.011), and Latin American ( P = 0.002) populations, but no conclusion could be reached for North America. The association between enterovirus infection and T1D was detected in blood and tissue samples (both P < 0.001); no association was found in stool samples., Conclusion: Our findings suggest that enterovirus infection is associated with T1D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Ye, Chen, Xu, Zhao, Wang and Lan.)

Enterovirus D68 (EV-D68) has emerged as an agent of epidemic respiratory illness and acute flaccid myelitis in the paediatric population but data are lacking in adult patients. We performed a 4.5-year single-centre retrospective study of all patients who tested positive for EV-D68 and analysed full-length EV-D68 genomes of the predominant clades B3 and D1. Between 1 June 2014, and 31 December 2018, 73 of the 11,365 patients investigated for respiratory pathogens tested positive for EV-D68, of whom 20 (27%) were adults (median age 53.7 years [IQR 34.0-65.7]) and 53 (73%) were children (median age 1.9 years [IQR 0.2-4.0]). The proportion of adults increased from 12% in 2014 to 48% in 2018 ( p = 0.01). All adults had an underlying comorbidity factor, including chronic lung disease in 12 (60%), diabetes mellitus in six (30%), and chronic heart disease in five (25%). Clade D1 infected a higher proportion of adults than clades B3 and B2 ( p = 0.001). Clade D1 was more divergent than clade B3: 5 of 19 amino acid changes in the capsid proteins were located in putative antigenic sites. Adult patients with underlying conditions are more likely to present with severe complications associated with EV-D68, notably the emergent clade D1.

We aimed to assess the duration of nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA persistence in adults self-confined at home after acute infection; and to identify the associations of SARS-CoV-2 persistence with respiratory virus co-detection and infection transmission. A cross-sectional intra-household study was conducted in metropolitan Barcelona (Spain) during the time period of April to June 2020. Every adult who was the first family member reported as SARS-CoV-2-positive by reverse transcription polymerase chain reaction (RT-PCR) as well as their household child contacts had nasopharyngeal swabs tested by a targeted SARS-CoV-2 RT-PCR and a multiplex viral respiratory panel after a 15 day minimum time lag. Four-hundred and four households (404 adults and 708 children) were enrolled. SARS-CoV-2 RNA was detected in 137 (33.9%) adults and 84 (11.9%) children. Rhinovirus/Enterovirus (RV/EV) was commonly found (83.3%) in co-infection with SARS-CoV-2 in adults. The mean duration of SARS-CoV-2 RNA presence in adults' nasopharynx was 52 days (range 26-83 days). The persistence of SARS-CoV-2 was significantly associated with RV/EV co-infection (adjusted odds ratio (aOR) 9.31; 95% CI 2.57-33.80) and SARS-CoV-2 detection in child contacts (aOR 2.08; 95% CI 1.24-3.51). Prolonged nasopharyngeal SARS-CoV-2 RNA persistence beyond the acute infection phase was frequent in adults quarantined at home during the first epidemic wave; which was associated with RV/EV co-infection and could enhance intra-household infection transmission.

Enteroviruses are associated with various diseases accompanied by rare but severe complications. In recent years, outbreaks of enterovirus D68 and enterovirus A71 associated with severe respiratory infections and neurological complications have been reported worldwide. Since information on molecular epidemiology in respiratory samples is still limited, the genetic diversity of enteroviruses was retrospectively analysed over a 4-year period (2013-2016) in respiratory samples from paediatric patients. Partial viral major capsid protein gene (VP1) sequences were determined for genotyping. Enteroviruses were detected in 255 (6.1%) of 4187 specimens. Phylogenetic analyses of 233 (91.4%) strains revealed 25 different genotypes distributed to Enterovirus A (39.1%), Enterovirus B (34.3%), and Enterovirus D (26.6%). The most frequently detected genotypes were enterovirus D68 (26.6%), coxsackievirus A6 (15.9%), and enterovirus A71 (7.3%). Enterovirus D68 detections were associated with lower respiratory tract infections and increased oxygen demand. Meningitis/encephalitis and other neurological symptoms were related to enterovirus A71, while coxsackievirus A6 was associated with upper respiratory diseases. Prematurity turned out as a potential risk factor for increased oxygen demand during enterovirus infections. The detailed analysis of epidemiological and clinical data contributes to the non-polio enterovirus surveillance in Europe and showed high and rapidly changing genetic diversity of circulating enteroviruses, including different enterovirus D68 variants.

Background: Although most enterovirus (EV) infections can be asymptomatic, these viral agents can cause serious conditions associated with central nervous system, respiratory disease and uncommon manifestations of hand, foot and mouth disease (HFMD). EV-coinfections have been rarely reported with development of complications and severe clinical outcome. An atypical case of a child presenting HFMD and severe acute respiratory syndrome, co-infected with EV-D68 and CVA6, is reported herein., Case Presentation: A 3-year-old boy was admitted in the emergency department unit showing fever, abdominal pain and tachycardia. Twenty-four hours after hospitalization the child developed severe clinical symptoms associated with HFMD and was discharged after recovery. Two days later, the child was readmitted with fever, cough and respiratory distress. RT-PCR and Sanger sequencing confirmed positivity for EV-D68 and CVA6 in oro and nasopharynges swabs and vesicles fluid, respectively. Phylogenetic analysis based on VP1 gene sequences suggested that CVA6 was closely related with HFMD viruses circulating in Turkey, while EV-D68 was genetically related to a Chinese strain., Conclusions: To the best of our knowledge, this case is the first report of a double infection caused by CVA6 and EV-D68, which shed light on the pathogenesis of enterovirus infections. Further studies must be conducted to ascertain the role and clinical significance of EV co-infections, as well as a potential synergistic pathway between these viruses.

The frequency of bacterial factors causing central nervous system infections has decreased as a result of the development of our national immunization program. In this study, it is aimed to obtain the data of our local surveillance by defining the viral etiology in cases diagnosed with meningoencephalitis for 1 year. Previously healhty 186 children, who applied with findings suggesting viral meningoencephalitis to 8 different tertiary health centers between August 2018 and August 2019, in Istanbul, were included. The cerebrospinal fluid (CSF) sample was evaluated by polymerase chain reaction. The M:F ratio was 1.24 in the patient group, whose age ranged from 1 to 216 months (mean 40.2 ± 48.7). Viral factor was detected in 26.8%. Enterovirus was the most common agent (24%) and followed by Adenovirus (22%) and HHV type 6 (22%). In the rest of the samples revealed HHV type 7 (10%), EBV (6%), CMV (6%), HSV type 1 (6%), Parvovirus (4%) and VZV (2%). The most common symptoms were fever (79%) and convulsions (45.7%). Antibiotherapy and antiviral therapy was started 48.6% and 4% respectively. Mortality and sequela rate resulted 0.53% and 3.7%, respectively. This highlights the importance of monitoring trends in encephalitis in Turkey with aview to improving pathogen diagnosis for encephalitis and rapidly identifying novel emerging encephalitis-causing pathogens that demand public health action especially in national immunisation programme.

Background: Enterovirus (EV) is a common cause of infection in neonates. Neonates are at high risk of enterovirus infection with serious clinical manifestations and high lethality. This review systematically summarized the clinical characteristics of neonates with severe enteroviral infection to provide evidence for the identification and treatment of severe neonatal EV infection., Methods: PubMed, Embase, and Web of Science were searched for original studies on neonates with severe EV infections from January 1, 2000, to November 27, 2020. Two reviewers independently screened the literature, extracted the data, and performed a descriptive analysis., Results: In total, 66 articles with 237 cases of severe neonatal enterovirus infection were included. All neonates developed severe complications. Among them, 46.0% neonates had hepatitis or coagulopathy, 37.1% had myocarditis, 11.0% had meningoencephalitis, and 5.9% had other complications such as hemophagocytic lymphohistiocytosis and pulmonary hemorrhage. The lethality rate of neonates with severe infection was 30.4%. The highest lethality rate was 38.6%, which was observed in neonates with myocarditis. In 70.5% neonates, the age at the onset of symptoms was less than 7 days. Coxsackievirus B infection was seen in 52.3% neonates. The most common symptoms included temperature abnormalities (127, 53.6%), rash (88, 37.1%), poor feeding (58, 24.5%), and respiratory symptoms (52, 21.9%). The main treatment included transfusion of empirical antibiotics (127, 53.6%), blood components (100, 42.2%), intravenous immunoglobulin (IVIG; 97, 40.9%), mechanical ventilation (51, 21.5%), and extracorporeal membrane oxygenation (ECMO; 43, 18.1%). Additionally, antiviral medications pleconaril (14, 5.9%) and pocapavir (3, 1.3%) were administered., Conclusions: Lethality was high in neonates with severe enterovirus infection, especially in those complicated with myocarditis. The most common symptoms included temperature abnormalities, rash, and poor feeding. The chief supportive treatment consisted of transfusion of blood components, mechanical ventilation, and ECMO. Empirical antibiotics and IVIG were widely used. Antiviral medications included pocapavir and pleconaril; however, more clinical evidence regarding their efficacy is needed.

Virus-induced asthma is prevalent among children, but its underlying mechanisms are unclear. Accumulated evidence indicates that early-life respiratory virus infection increases susceptibility to allergic asthma. Nonetheless, the relationship between systemic virus infections, such as enterovirus infection, and the ensuing effects on allergic asthma development is unknown. Early-life enterovirus infection was correlated with higher risks of allergic diseases in children. Adult mice exhibited exacerbated mite allergen-induced airway inflammation following recovery from EV-A71 infection in the neonatal period. Bone marrow-derived macrophages (BMDMs) from recovered EV-A71-infected mice showed sustained innate immune memory (trained immunity) that could drive naïve T helper cells toward Th2 and Th17 cell differentiation when in contact with mites. Adoptive transfer of EV-A71-trained BMDMs induced augmented allergic inflammation in naïve recipient mice, which was inhibited by 2-deoxy-D-glucose (2-DG) pretreatment, suggesting that trained macrophages following enterovirus infection are crucial in the progression of allergic asthma later in life.

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the FUT2 and FUT3 genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.

The current SARS-CoV-2 pandemic has caused a huge global public health problem. We report the case of a young adult patient with laboratory-confirmed SARS-CoV-2. We describe the identification of the virus and the clinical course, diagnosis, and treatment of the infection including her rapid clinical deterioration from the mild initial symptoms, which progressed to multilobar pneumonia requiring admission to the intensive care unit. This case highlights the importance of establishing a diagnosis based on the clinical findings and the patient’s history bearing in mind the possibility of gastrointestinal symptoms in addition to respiratory ones. Besides, the presence of risk factors should be investigated; in this case, we proposed obesity as a possible risk factor. Furthermore, limitations in diagnostic tests and the possibility of co-infection with other respiratory pathogens are highlighted. We describe the imaging, laboratory findings, and treatment taking into account the limited current evidence.

Major 5'terminally deleted (5'TD) group-B enterovirus (EV-B) populations were identified in heart biopsies of patients with fulminant myocarditis or dilated cardiomyopathy suggesting that these 5'TD forms are key drivers of host-cell interaction in EV cardiac infections. To date, early emergence of EV-B 5'TD forms and its impact on type 1 IFN response during acute myocarditis remains unknown. Using quantitative RACE-PCR assay, we identified major EV-B 5'TD RNA populations in plasma or heart samples of acute myocarditis cases. Deletions identified within the 5' non-coding region of EV-B populations only affected secondary-structural elements of genomic RNA domain I and were distinguished in two major groups based on the extent of RNA structural deletions. Proportions of these two respective EV-B 5'TD population groups were positively or negatively correlated with IFN-β levels in plasma samples of myocarditis patients. Transfection of synthetic CVB3/28 RNAs harboring various 5'terminal full-length or deleted sequences into human cultured cardiomyocytes demonstrated that viral genomic RNA domain I possessed essential immunomodulatory secondary-structural elements responsible for IFN-β pathway induction. Overall, our results highlight the early emergence of major EVB-TD populations which deletions affecting secondary-structures of RNA domain I can modulate innate immune sensing mechanisms in cardiomyocytes of patients with acute myocarditis.

Using immunohistochemistry, enterovirus capsid proteins were demonstrated in pancreatic islets of patients with type 1 diabetes. Virus proteins are mainly located in beta cells, supporting the hypothesis that enterovirus infections may contribute to the pathogenesis of type 1 diabetes. In samples of pancreatic tissue, enterovirus RNA was also detected, but in extremely small quantities and in a smaller proportion of cases compared to the enteroviral protein. Difficulties in detecting viral RNA could be due to the very small number of infected cells, the possible activity of PCR inhibitors, and the presence-during persistent infection-of the viral genome in unencapsidated forms. The aim of this study was twofold: (a) to examine if enzymes or other compounds in pancreatic tissue could affect the molecular detection of encapsidated vs. unencapsidated enterovirus forms, and (b) to compare the sensitivity of RT-PCR methods used in different laboratories. Dilutions of encapsidated and unencapsidated virus were spiked into human pancreas homogenate and analyzed by RT-PCR. Incubation of pancreatic homogenate on wet ice for 20 h did not influence the detection of encapsidated virus. In contrast, a 15-min incubation on wet ice dramatically reduced detection of unencapsidated forms of virus. PCR inhibitors could not be found in pancreatic extract. The results show that components in the pancreas homogenate may selectively affect the detection of unencapsidated forms of enterovirus. This may lead to difficulties in diagnosing persisting enterovirus infection in the pancreas of patients with type 1 diabetes.

Purpose: SCN1A variants cause a spectrum of epilepsy syndromes from Dravet Syndrome, a severe epileptic encephalopathy of early infancy to the milder disorder of genetic epilepsy with febrile seizures plus (GEFS+). These genetic epilepsies are associated with increased risk of poor outcome including complications of status epilepticus and early mortality. Individualised management of young children known to be at increased risk should be considered, such as around vaccination management., Methods: We describe two siblings with a novel pathogenic SCN1A variant, their management and clinical outcomes following routine childhood vaccinations., Results: The index case who had a family history of epilepsy of unknown genetic aetiology, died from hypoxic ischemic encephalopathy following his 12-month vaccinations, in the context of status epilepticus and enterovirus 71 infection. The sibling of the index case with the same SCN1A variant was subsequently managed with prophylactic regular sodium valproate and additional clobazam post vaccination to reduce the risk of seizure. She has successfully completed the childhood immunisations to 18 months with no seizures and normal neurodevelopmental progress., Conclusion: As the aetiology of genetic epilepsies is increasingly known in early childhood, opportunities to personalise care, minimise risks and optimise outcomes are changing. Further research is needed on the risks and benefits of symptomatic and preventative management of seizures around vaccinations in young children with genetic epilepsies., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Background and objective : Enterovirus 71 (EV 71) infections may result in the rapid progression of cardiopulmonary failure. Early endotracheal intubation is considered to be of primary importance. However, the appropriate timing for this is still not known. The aim of this study is to investigate the timing of intubation of children with fulminant EV71 infection. Material and Methods : From March 1998 to May 2012, patients with severe EV71 infection who were admitted to the pediatric intensive care unit of the National Cheng Kung University Hospital were enrolled in this study. Medical records were retrospectively reviewed. The patients were classified into three groups in accordance with the outcome of intubation. We used rhombencephalitis grading to describe the neurological presentation of these patients. The study was approved by the institutional review board. Results : There were a total of 105 patients enrolled. Of these, 77 patients were in Grade I, and only three of them needed intubation, who were, however, soon extubated within 24 h. There were 10 patients in Grade II; nine of them needed intubation. In total, 18 patients belonged to Grade III, and all of them need to be intubated. We then compared the outcome of intubation of grades II and III. There was only one patient out of the nine patients in grade II who experienced failed extubation due to the progression of the disease. Among grade III patients, only four patients were successfully extubated. We also listed clinical parameters to determine which one could be a sign that indicated intubation. Comparing the favorable outcomes, cranial nerve involvement was a good indicator for the timing of intubation. Conclusions : This study showed that early intubation in Grade II provides favorable outcomes and improves morbidity and mortality. We also found that if cranial nerve involvement was present, then early intubation is indicated.

Background: Enterovirus-D68 (EV-D68) has been endemic in Taiwan for some years with a small number of positive cases. Detailed information about respiratory presentation is lacking. This study characterized the clinical course in children admitted to the medical center and regional hospital in Taichung during 2015., Methods: Retrospective chart review of patients with confirmed EV-D68 infection admitted to the medical center and regional hospital in Taichung with respiratory symptoms in the second half of 2015. Past medical history, clinical presentation, management, and course in hospital were collected and analyzed. Simple demographic data and clinical symptoms were also collected from patients confirmed with EV-D68 infection who visited clinics in Taichung., Results: Six children were included. Two patients had a prior history of asthma or recurrent dyspnea, and one had other preexisting medical comorbidities. One child was admitted to the pediatric intensive care unit. All the patients were cured. Cough, rhinorrhea, tachypnea and fever were the most common clinical symptoms among inpatients, while influenza-like illness (ILI) was prevalent in outpatients., Conclusion: EV-D68 infection resulted in respiratory presentations of asthma-like illness in the hospitalized pediatric population. Patients with a prior history of asthma or recurrent dyspnea appear to be more severely affected., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Severe hand, foot, and mouth disease (HFMD) is associated with high mortality in children, and persistent sympathetic activation is a common presentation. The aim of this study was to prospectively investigate serum chromogranin A (CHGA) levels and their prognostic role in this condition., Methods: Serum CHGA, creatine kinase myocardial band (CK-MB), serum D-dimer, norepinephrine, blood glucose, lactate, and C-reactive protein levels, white blood cell (WBC) counts, usage of vasopressors, pediatric risk of mortality Ⅲ (PRISM-Ⅲ) scores, and viral etiology were measured upon pediatric intensive care unit (PICU) admission. The correlation between clinical outcomes and the indicators listed above were analyzed, and the ability of CHGA as a biomarker to predict mortality was evaluated., Results: Serum CHGA levels were higher in the non-survivors group than in the survivors group (median (interquartile range): 434.8 (374.3-502.4) vs 183.3 (131.9-246.9) μg/l; p < 0.001) and were correlated with norepinephrine (r = 0.37. p < 0.001), blood glucose (r = 0.32, p = 0.001), lactate (r = 0.25, p = 0.009), WBC (r = 0.20, p = 0.039), and PRISM-Ⅲ scores (r = 0.748, p < 0.0001). Patients suffering neurogenic pulmonary edema, those infected with enterovirus A71, and those requiring more vasopressors had higher serum CHGA levels (median (interquartile range): 385 (239.9-488.8) vs 161 (115.6-222.9), 340.6 (190.6-436.0) vs 150.5 (112.1-210.0), 395.6 (209.1-487.0) vs 167.7 (110.5-240.5) μg/l, respectively; p < 0.0001). The CHGA level upon PICU admission in severe HFMD could be an independent risk factor for mortality (adjusted odds ratio 2.459, 95% confidence interval 1.054-5.906, p = 0.038) with high specificity (87.5%) and sensitivity (82.6%) (cut-off value at 339.6 μg/l)., Conclusions: The CHGA level in severe HFMD was found to be associated with cardiopulmonary failure. If measured upon PICU admission, CHGA may provide additional prognostic information in this disease., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Coxsackievirus group B (CVB) contains six serotypes that can affect various organs. Some of these organ-specific diseases such as myocarditis and pancreatitis can be caused by more than one serotype. Thus, development of immunological tools common to multiple serotypes is desired. This is especially critical for analyzing antigen-specific T cell responses at a single cell level. To this end, we made efforts to identify the immunogenic epitopes of CVB3 leading us to localize three T cell epitopes within the viral protein 1 (VP1) namely, VP1 681-700, VP1 721-740 and VP1 771-790. First, we confirmed their immunogenicity in the immunization settings. Second, we sought to verify the ability of VP1 epitopes to bind major histocompatibility complex (MHC) class II (IA k ) molecules. Third, we created MHC class II (IA k ) dextramers and tetramers and ascertained the T cell responses to be antigen-specific. Fourth, we analyzed the T cell responses in animals infected with CVB3 and noted the magnitude of antigen-specific T cell responses occurring in the order of VP1 721-740 and VP1 681-700 followed by VP1 771-790 as verified by proliferation assay and IA k tetramer staining. All epitopes induced interferon (IFN)-γ as a major cytokine. Finally, we investigated whether the VP1 tools generated for CVB3 can also be used to verify T cell responses in infections caused by other serotypes. To this end, we established the CVB4 infection model in A/J mice and found that the CVB4 infection led to the induction of IFN-γ-producing T cell responses primarily for VP1 721-740 and VP1 681-700. Thus, the VP1-specific tools, particularly IA k tetramers can be used to monitor anti-viral T cell responses in multiple CVB serotypes.

Observed peaks of acute flaccid myelitis (AFM) cases have occurred biennially since 2014 in the United States. We aimed to determine if AFM etiology differed between peak and nonpeak years, considering that clinical features of AFM differ by virus etiology. We compared clinical and laboratory characteristics of AFM cases that occurred during peak (2016 and 2018, n = 366) and nonpeak (2015 and 2017, n = 50) years. AFM patients in peak years were younger (5.2 years) than those in nonpeak years (8.3 years). A higher percentage of patients in peak years than nonpeak years had pleocytosis (86% vs. 60%), upper extremity involvement (33% vs. 16%), and an illness preceding limb weakness (90% vs. 62%) and were positive for enterovirus or rhinovirus RNA (38% vs. 16%). Enterovirus D68 infection was associated with AFM only in peak years. Our findings suggest AFM etiology differs between peak and nonpeak years.

Enterovirus D68 was first identified in 1962 and caused a worldwide outbreak starting from the North America in 2014. Enterovirus D68 has been in continuous circulation among many countries recently, including Taiwan. Reports also reveal high seroprevalence, which indicates that the disease burden of enterovirus D68 may be underestimated via viral culture or polymerase chain reaction results. Although most infected cases have mild respiratory illness, severe complications including acute flaccid myelitis and acute respiratory distress syndrome have also been reported. In the position of an emerging pathogen, enterovirus D68 poses a threat to public health and may cause devastating diseases. Diverse severity of neurological sequelae remains inevitable among acute flaccid myelitis patients, but no curable treatment is available currently. According to the management suggestions of the American Centers of Disease Control, uses of corticosteroids and plasmapheresis are either preferred or avoided and intravenous immunoglobulin also has no clear indication in the treatment for acute flaccid myelitis. In this review article, we provide information about the epidemiology, clinical recognition and treatment strategy of enterovirus D68. Better understanding of this disease is the foothold for advanced investigation and monitoring in the future., (Copyright © 2019. Published by Elsevier B.V.)

Enteroviruses (EVs) are the most common human pathogens worldwide. Recent international outbreaks in North America and South East Asia have emphasized the need for more effective anti-viral therapies. As obligate parasites, EVs rely on the host cellular machinery for effective viral propagation. Accumulating evidence has indicated that EVs subvert and disrupt the cellular autophagy pathway to facilitate productive infection, and consequently leading to host pathogenesis. Given that defective autophagy is a common factor in various human diseases, including neurodegeneration, cardiomyopathy, and metabolic disorders, a clear understanding of the relationship between EV infection and autophagy is warranted. In this review, we highlight recent advances in understanding the molecular mechanisms by which EVs exploit the autophagy pathway during different steps of viral life cycle, from entry, replication, and maturation to release. We also provide an overview of recent progress in EV subversion of the autophagy for immune evasion.

Purpose: The seasonal distribution patterns of febrile seizures and of respiratory and enteric viral pathogens are similar. In this study, we analyzed trends in febrile seizures and viral infection in Korean children, using big data from the Korean Health Insurance Review and Assessment Service (HIRA)., Methods: We analyzed children younger than 6 years who visited the hospital and were diagnosed with febrile seizures from 2009 to 2016, using medical records in the HIRA database. A total of 666,136 medical records of children with a main or subdiagnosis of febrile seizure from 2008 to 2016 were included. Of these records, patients younger than 1 month and records before 2009 were excluded. Finally, 558,130 records were extracted., Results: The medical records included 315,774 male children and 242,356 (43.4%) female children, with a mean age of 2.31 ± 1.31 years. The annual incidence of febrile seizure was 25.4 per 1000 person-years (27.9 for boys and 22.7 for girls). The ratio of male to female children was 1.30: 1, and records of 1-year-old children comprised the highest proportion (n = 210,400, 33.70%). The total monthly number of patients was highest in May (n = 64,969, 11.6%), and peaks were formed from April to July. The fewest patients were seen in October (n = 34,424, 6.17%). The most common viral pathogens were influenza in April and enterovirus during May-July., Conclusion: The seasonal distribution of febrile seizures was high from late spring to summer, and influenza virus and enterovirus were most frequently associated., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)