Search

Enterovirus-D68 (EV68) has emerged as a global health concern over the last decade with severe symptomatic infections resulting in long-lasting neurological deficits and death. Unfortunately, there are currently no FDA-approved antiviral drugs for EV68 or any other non-polio enterovirus. One particularly attractive class of potential drugs are small molecules inhibitors, which can target the conserved active site of EV68-3C protease. For other viral proteases, we have demonstrated that the emergence of drug resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of substrate specificity. However, the structural characterization of EV68-3C protease bound to its substrates has been lacking. Here, we have determined the substrate specificity of EV68-3C protease through molecular modeling, molecular dynamics (MD) simulations, and co-crystal structures. Molecular models enabled us to successfully characterize the conserved hydrogen-bond networks between EV68-3C protease and the peptides corresponding to the viral cleavage sites. In addition, co-crystal structures we determined have revealed substrate-induced conformational changes of the protease which involved new interactions, primarily surrounding the S1 pocket. We calculated the substrate envelope, the three-dimensional consensus volume occupied by the substrates within the active site. With the elucidation of the EV68-3C protease substrate envelope, we evaluated how 3C protease inhibitors, AG7088 and SG-85, fit within the active site to predict potential resistance mutations.

Background: Respiratory viral infections are common in febrile infants ≤90 days. However, the detection of viruses other than enterovirus in the blood and cerebrospinal fluid (CSF) of young infants is not well defined. We sought to quantify the occurrence of respiratory viruses in the blood and CSF of febrile infants ≤90 days. Methods: We conducted a nested cohort study examining plasma and CSF samples from febrile infants 15–90 days via rtPCR. The samples were tested for respiratory viruses (respiratory syncytial virus, influenza, enterovirus, parechovirus, adenovirus, bocavirus). Clinical and laboratory data were also collected to determine the presence of serious bacterial infections (SBI). Results: Twenty‐four percent (30 of 126) of infants had plasma/CSF specimens positive for a respiratory virus. Enterovirus and parechovirus were the most commonly detected respiratory viruses. Viral positivity was highest in plasma samples at 25% (27 of 107) compared with CSF samples at 15% (nine of 62). SBIs (specifically urinary tract infections) were less common in infants with a sample positive for a respiratory virus compared to those without a virus detected (3% vs. 26%, p = 0.008). Conclusions: Our findings support the use of molecular diagnostics to include the identification of parechovirus in addition to enterovirus in febrile infants ≤90 days. Additionally, these data support the utilization of blood specimens to diagnose enterovirus and parechovirus infections in febrile infants ≤90 days. [ABSTRACT FROM AUTHOR]

Human enteroviruses (EV) are the most common cause of aseptic meningitis worldwide. Data on EV viral load in cerebrospinal fluid (CSF) and related epidemiological studies are scarce in Brazil. This study investigated the influence of EV viral load on CSF parameters, as well as identifying the involved species. CSF samples were collected in 2018–2019 from 140 individuals at The Hospital das Clínicas, São Paulo. The EV viral load was determined using real‐time quantitative polymerase chain reaction, while EV species were identified by 5′UTR region sequencing. Median viral load was 5.72 log10 copies/mL and did not differ by subjects' age and EV species. Pleocytosis was observed in 94.3% of cases, with the highest white blood cell (WBC) counts in younger individuals. Viral load and WBC count were correlated in children (p = 0.0172). Elevated lactate levels were observed in 60% of cases and correlated with the viral load in preteen‐teenagers (p = 0.0120) and adults (p = 0.0184). Most individuals had normal total protein levels (70.7%), with higher in preteen‐teenagers and adults (p < 0.0001). By sequencing, 8.2% were identified as EV species A and 91.8% as species B. Age‐specific variations in CSF characteristics suggest distinct inflammatory responses in each group. [ABSTRACT FROM AUTHOR]

Intestinal tuft cells, a kind of epithelial immune cells, rapidly expand in response to pathogenic infections, which is associated with infection‐induced interleukin 25 (IL‐25) upregulation. However, the metabolic mechanism of IL‐25‐induced tuft cell expansion is largely unknown. Folate metabolism provides essential purine and methyl substrates for cell proliferation and differentiation. Thus, we aim to investigate the roles of folate metabolism playing in IL‐25‐induced tuft cell expansion by enteroviral infection and recombinant murine IL‐25 (rmIL‐25) protein‐stimulated mouse models. At present, enteroviruses, such as EV71, CVA16, CVB3, and CVB4, upregulated IL‐25 expression and induced tuft cell expansion in the intestinal tissues of mice. However, EV71 did not induce intestinal tuft cell expansion in IL‐25−/− mice. Interestingly, compared to the mock group, folate was enriched in the intestinal tissues of both the EV71‐infected group and the rmIL‐25 protein‐stimulated group. Moreover, folate metabolism supported IL‐25‐induced tuft cell expansion since both folate‐depletion and anti‐folate MTX‐treated mice had a disrupted tuft cell expansion in response to rmIL‐25 protein stimulation. In summary, our data suggested that folate metabolism supported intestinal tuft cell expansion in response to enterovirus‐induced IL‐25 expression, which provided a new insight into the mechanisms of tuft cell expansion from the perspective of folate metabolism. [ABSTRACT FROM AUTHOR]

Background: Japanese encephalitis (JE) is a notifiable infectious disease in China. Information on every case of JE is reported to the superior health administration department. However, reported cases include both laboratoryconfirmed and clinically diagnosed cases. This study aimed to differentiate between clinical and laboratory-confirmed cases of Japanese encephalitis virus (JEV) infection, and improve the accuracy of reported JE cases by analyzing the acute-phase serum and cerebrospinal fluid of all reported JE cases in the Sichuan province from 2012 to 2022. Methods: All acute-phase serum and/or cerebrospinal fluid samples of the reported JE cases were screened for IgM(ImmunoglobulinM)to JEV using the enzyme-linked immunosorbent assay (ELISA), and the detection of the viral genes of JEV and 9 other pathogens including enterovirus (EV), using reverse transcription PCR was attempted. Epidemiological analyses of JE and non-JE cases based on sex, age, onset time, and geographical distribution were also performed. Results: From 2012 to 2022, 1558 JE cases were reported in the Sichuan province. The results of serological (JEV-specific IgM) and genetic testing for JEV showed that 81% (1262/1558) of the reported cases were confirmed as JEV infection cases (laboratory-confirmed cases). Among the 296 cases of non-JEV infection, 6 viruses were detected in the cerebrospinal fluid in 62 cases, including EV and the Epstein-Barr virus (EBV), constituting 21% (62/296) of all non-JE cases. Among the 62 non-JEV infection cases with confirmed pathogens, infections with EV and EBV included 17 cases each, herpes simplex virus (HSV-1/2) included 14 cases, varicella- zoster virus included 6 cases, mumps virus included 2 cases, and human herpes viruses-6 included 1 case. Additionally, there were five cases involving mixed infections (two cases of EV/EBV, one case of HSV-1/HSV-2, one case of EBV/HSV-1, and one case of EV/herpes viruses-6). The remaining 234 cases were classified as unknown viral encephalitis cases. Our analysis indicated that those aged 0–15 y were the majority of the patients among the 1558 reported JE cases. However, the incidence of laboratory-confirmed JE cases in the >40 y age group has increased in recent years. The temporal distribution of laboratory-confirmed cases of JE revealed that the majority of cases occurred from May to September each year, with the highest incidence in August. Conclusion: The results of this study indicate that there is a certain discrepancy between clinically diagnosed and laboratory-confirmed cases of JE. Each reported case should be based on laboratory detection results, which is of great importance in improving the accuracy of case diagnosis and reducing misreporting. Our results are not only important for addressing JE endemic to the Sichuan province, but also provide a valuable reference for the laboratory detection of various notifiable infectious diseases in China and other regions outside China. [ABSTRACT FROM AUTHOR]

Background: Enteroviruses have the potential to cause both high morbidity and mortality especially in children. High season in Norway is between August and November, but this seasonality was interrupted by the COVID-19 pandemic. Methods: In this study, we describe the enterovirus surveillance in Norway before and during the COVID-19 pandemic including the years from the start of 2016 until the end of 2022. Screening of enterovirus was performed by both laboratory developed methods and FilmArray® ME Panel. Relevant samples were typed, mostly by VP1 sequencing. Results: Seventy-four percent of all cases occurred in infants under five years of age. A significant reduction in positive cases was observed during the peak years of the COVID-19 pandemic compared to the years before. Pre-pandemic, a wide range of types from all four enterovirus species were detected. During the years with COVID-19 infection control measures, significantly fewer enterovirus types were found along with a substantial reduction in the detection rate. Conclusion: Enterovirus surveillance discovered a large amount of different types mainly affecting infants. The positivity rate was markedly reduced during the pandemic in 2020-2022 and fewer types occurred. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of antiviral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-andrun scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: A Meningitis and Encephalitis Surveillance (MERIN) was implemented in 2003 in Lower Saxony, Germany as an alternative to acute flaccid paralyses surveillance, as the latter did not reach WHO sensitivity criteria. The system provides information on circulating enterovirus (EV) serotypes by focussing on patients with suspected aseptic meningitis, encephalitis or acute flaccid paralysis and contributes to the national surveillance in documenting polio free status. MERIN is based on voluntary participation of hospitals. Therefore, our evaluation focusses on acceptability of the system's objectives and performance, and identifying areas for improvement. Methods: To assess acceptability, 32 contributing hospitals were invited to an online-based survey (11/2021 to 01/2022) to rate the MERIN objectives, laboratory's performance, their workload, modes of processes and communication. Ideas for improvement were collected in open fields. In addition, data completeness and timeliness of laboratory diagnostics were assessed. Results: Of 32 hospitals, 21 responded (66% response rate), sending 30 questionnaires, 25 from pediatric and 5 from neurological departments. High levels of satisfaction with the communication (≥ 96%), timeliness (≥ 81%), and distribution of the results (≥ 85%) were reported, 97% of participants judged the required workload as adequate. The median proportion of eligible patients included in MERIN was 75%. Participants gave rapid and reliable diagnostic testing the highest priority (96%), while monitoring of Germany's polio-free status was rated the lowest (61%). Providing medical reports digitally as well as regular updates about circulating EV serotypes were identified as areas for improvement. Data completeness of selected variables ranged from 78.3 to 99.9%. Median time between sample collection and arrival at laboratory was 2 days [IQR 1–3], EV diagnostics via PCR took one day [IQR 0–6] and EV isolation on cell culture 11 days [IQR 10–13]. Conclusion: MERIN is a highly accepted surveillance system. Its quality was enhanced further by addressing the suggested improvements such as regular reports on circulating EV serotypes and facilitating digital access to laboratory results. Our results emphasise the importance of recognizing and considering participants' motivations and expectations, and addressing their priorities, even if this is not the surveillance system's main focus. This approach can be applied to surveillance systems of other non-mandatory notifiable diseases. [ABSTRACT FROM AUTHOR]

Introduction: We describe the first case of acute flaccid myelitis (AFM) related to enterovirus D68 (EV-D68) infection in Belgium. The clinical and radiological presentation of AFM associated with EV-D68 although well described currently remains a challenging diagnosis. Through this interesting clinical case, we aimed to review the differential diagnosis of acute flaccid palsy in a child and discuss the specific point of interest related to AFM. Case Presentation: We present the case of a 4-year-old girl with a torticollis associated with an acute palsy of the right upper limb. The magnetic resonance imaging revealed an increased T2 signal intensity of the entire central gray matter of the cervical cord with involvement of the posterior brainstem. A polymerase chain reaction (PCR) conducted on a nasopharyngeal swab was found positive for EV-D68. The definition of AFM proposed by the Center for Disease Control and Prevention (CDC) is an acute-onset flaccid weakness of one or more limbs in the absence of a clear alternative diagnosis and the radiological evidence of gray matter involvement on an MRI picture, and our case fits these two criteria. A prompt and detailed workup is required to distinguish this emergent disease from other forms of acute flaccid palsy. The functional prognosis of AFM is poor, and there are no evidence-based treatment guidelines so far. Conclusion: AFM is an emerging pathology that requires the attention of pediatricians to quickly rule out differential diagnoses and adequately manage the patient. Further research is needed to optimize treatments, improve outcomes, and provide scientifically based guidelines. [ABSTRACT FROM AUTHOR]

Nonpharmaceutical interventions (NPIs) for coronavirus disease 2019 (COVID‐19) not only reduce the prevalence of this disease among children but also influence the transmission of other viruses. This retrospective study investigated the impact of NPIs on human enterovirus (HEV) infection in children diagnosed with hand, foot, and mouth disease (HFMD) or herpangina (HA) in Hangzhou, China. We collected and analyzed the laboratory results and clinical data of children diagnosed with HFMD or HA during the following periods: pre‐COVID‐19 (January 2019 to December 2019), the COVID‐19 pandemic (January 2020 to December 2022), and post‐COVID‐19 (January to December 2023). A total of 41 742 specimens that met the inclusion criteria were obtained, of which 1998 (4.79%) tested positive for enterovirus. In comparison to those in the pre‐COVID‐19 period, which had 695 (5.63%) HEV‐positive specimens, the numbers dramatically decreased to 69 (1.19%), 398 (5.12%), and 112 (1.58%) in 2020, 2021, and 2022, respectively, but significantly increased to 724 (8.27%) in 2023. Seasonal peaks of infections occurred in May, June, July, and August each year, with the total detection rate ranging from 2019 to 2023 being 9.41% in May, 22.47% in June, 28.23% in July, and 12.16% in August, respectively. The difference in the detection rates of HEV infection between males and females was statistically significant (p < 0.005), with 5.11% (1221/23 898) of males and 4.35% (777/17 844) of females testing positive, resulting in a male‐to‐female positive ratio of 1.57:1. Among the age groups, 11.25% (378/3360) of the children aged 3–5 years had the highest detection rate, which steadily decreased with increasing or decreasing age. The detection of HEV indicated that >95% of the viruses were other types than the previously commonly reported enterovirus 71 (EV‐A71) and coxsackievirus A16 (CV‐A16). In conclusion, NPIs for COVID‐19 may be effective at reducing the transmission of HEV. However, with the relaxation of NPIs, the detection rate of HEVs increased slowly to a certain extent. Active awareness and surveillance of the epidemiological characteristics of HEV are essential for preventing, controlling, and managing the development of HFMD and HA, as well as contributing to the development of a multivalent HFMD vaccine. [ABSTRACT FROM AUTHOR]

Enteroviruses (EVs), single‐stranded, positive‐sense RNA viruses, can be classified into four species (A−D), which have previously been linked to a diverse range of disease manifestations and infections affecting the central nervous system. In the Enterovirus species B (EV‐B), Echovirus type 11 (E11) has been observed to occasionally circulate in Taiwan, which was responsible for an epidemic of enterovirus infections in 2018. Here, 48 clinical specimens isolated in 2003, 2004, 2009, and 2018 were collected for the high‐throughput sequencing. Notably, we identified 2018 Taiwanese strains having potential recombinations in the 3D gene, as well as one 2003 strain having a double recombination with E6 and Coxsackievirus B5 in the P2 and P3 regions, respectively. Additionally, one amino acid signature mutated from the Histidine (H) in throat swab specimens to the Tyrosine (Y) in cerebral spinal fluid specimens was detected at position 1496 (or 57) of the genomic coordinate (or 3A gene) to further demonstrate intra‐host evolution in different organs. In conclusion, this study identifies potential intertypic recombination events and an intra‐host signature mutation in E11 strains, isolated during a 2018 neurological disease outbreak in Taiwan, contributing to our understanding of its evolution and pathogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Utilization of time series forecasting models as prediction tools for HFMD have been well studied for years. However, their forecasting performance and reliability during the recent COVID-19 pandemic remained unclear. Therefore, the aim of this study is to develop a pre-pandemic fitted time series forecasting model for HFMD, to study the model's forecasting performance before and during the pandemic. Methods: SARIMAX model was developed using weekly HFMD surveillance data, Google Trends data, and meteorological data for Tawau, Sabah from 2013 - 2020. The model was trained using pre-pandemic dataset (2013 - 2019) and tested with dataset during the pandemic (2020). Mean average percentage error (MAPE) and root mean square error (RMSE) were used as validation metrics to compare the accuracy of the model before and during pandemic. Results: SARIMA (1,0,1) (0,1,1) [52] with external regressors using real time Google Trends, mean, maximum temperature and relative humidity at lag 4 weeks was the best performing model with AIC value of 1348.45. The model can forecast HFMD cases with relatively stable decay in accuracy up to 8 weeks (pre-pandemic), before declining sharply during the beginning of the pandemic at week 10 to 12. Conclusion: Forecasting HFMD cases during COVID-19 pandemic was challenging in terms of forecasting accuracy due to the unexpected changes in HFMD trend throughout the first year of the pandemic. Therefore, there is a need to revise previous or current models, and to take into consideration the changes in HFMD trend during the pandemic for future model development. [ABSTRACT FROM AUTHOR]

BackgroundNeonatal (enteroviral) myocarditis (NM/NEM) is rare but unpredictable and devastating, with high mortality and morbidity. We report a case of neonatal coxsackievirus B (CVB) fulminant myocarditis successfully treated with veno-arterial extracorporeal membrane oxygenation (V-A ECMO).Case presentationA previously healthy 7-day-old boy presented with fever for 4 days. Progressive cardiac dysfunction (weak heart sounds, hepatomegaly, pulmonary edema, ascites, and oliguria), decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS), transient ventricular fibrillation, dramatically elevated creatine kinase-MB (405.8 U/L), cardiac troponin I (25.85 ng/ml), and N-terminal pro-brain natriuretic peptide (NT-proBNP > 35,000 ng/L), and positive blood CVB ribonucleic acid indicated neonatal CVB fulminating myocarditis. It was refractory to mechanical ventilation, fluid resuscitation, inotropes, corticosteroids, intravenous immunoglobulin, and diuretics during the first 4 days of hospitalization (DOH 1–4). The deterioration was suppressed by V-A ECMO in the next 5 days (DOH 5–9), despite the occurrence of bilateral grade III intraventricular hemorrhage on DOH 7. Within the first 4 days after ECMO decannulation (DOH 10–13), he continued to improve with withdrawal of mechanical ventilation, LVEF > 60%, and FS > 30%. In the subsequent 4 days (DOH 14–17), his LVEF and FS decreased to 52% and 25%, and further dropped to 37%–38% and 17% over the next 2 days (DOH 18–19), respectively. There was no other deterioration except for cardiomegaly and paroxysmal tachypnea. Through strengthening fluid restriction and diuresis, and improving cardiopulmonary function, he restabilized. Finally, notwithstanding NT-proBNP elevation (>35,000 ng/L), cardiomegaly, and low LVEF (40%–44%) and FS (18%–21%) levels, he was discharged on DOH 26 with oral medications discontinued within 3 weeks postdischarge. In nearly three years of follow-up, he was uneventful, with interventricular septum hyperechogenic foci and mild mitral/tricuspid regurgitation.ConclusionsDynamic cardiac function monitoring via real-time echocardiography is useful for the diagnosis and treatment of NM/NEM. As a lifesaving therapy, ECMO may improve the survival rate of patients with NM/NEM. However, the “honeymoon period” after ECMO may cause the illusion of recovery. Regardless of whether the survivors of NM/NEM have undergone ECMO, close long-term follow-up is paramount to the prompt identification and intervention of abnormalities.

Objectives: Following the alert of echovirus 11 (E-11) infection in neonates in EU/EEA Member States, we conducted an investigation of E-11 circulation by gathering data from community and hospital surveillance of enterovirus (EV) in northern Italy from 01 August 2021 to 30 June 2023. Methods: Virological results of EVs were obtained from the regional sentinel surveillance database for influenza-like illness (ILI) in outpatients, and from the laboratory database of ten hospitals for inpatients with either respiratory or neurological symptoms. Molecular characterization of EVs was performed by sequence analysis of the VP1 gene. Results: In our ILI series, the rate of EV-positive specimens showed an upward trend from the end of May 2023, culminating at the end of June, coinciding with an increase in EV-positive hospital cases. The E-11 identified belonged to the D5 genogroup and the majority (83%) were closely associated with the novel E-11 variant, first identified in severe neonatal infections in France since 2022. E-11 was identified sporadically in community cases until February 2023, when it was also found in hospitalized cases with a range of clinical manifestations. All E-11 cases were children, with 14 out of 24 cases identified through hospital surveillance. Of these cases, 60% were neonates, and 71% had severe clinical manifestations. Conclusion: Baseline epidemiological data collected since 2021 through EV laboratory-based surveillance have rapidly tracked the E-11 variant since November 2022, alongside its transmission during the late spring of 2023.

Enterovirus A71 (EV-A71) is among the most neuropathogenic non-polio enterovirus types and, in rare instances, can lead to severe or even fatal outcomes, particularly in children under 5 years of age. This case study presents clinical and microbiological findings from the initial documented severe pediatric EV-A71 case in Finland, identified in May 2019. The near-complete genome sequence confirms that the EV-A71 strain belongs to the newly identified recombinant C1-like EV-A71 genetic lineage, which emerged in 2015 and has since been circulating in Europe, causing severe cases among children in various European countries. Enhanced environmental surveillance revealed widespread circulation of EV-A71 in Finland in 2019. However, the overall number of EV clinical cases remained lower than in previous years.

Enterovirus is not a common cause of myositis and rhabdomyolysis in children. We report a case of a two-year-old boy with acute lymphoblastic leukemia with disseminated enterovirus infection complicated by hepatitis, myositis, and rhabdomyolysis. The case was managed successfully with supportive care and high-dose intravenous immunoglobulins.

ABSTRACTEnteric infections are important causes of morbidity and mortality, yet clinical surveillance is limited. Wastewater-based epidemiology (WBE) has been used to study community circulation of individual enteric viruses and panels of respiratory diseases, but there is limited work studying the concurrent circulation of a suite of important enteric viruses. A retrospective WBE study was carried out at two wastewater treatment plants located in California, United States. Using digital droplet polymerase chain reaction (PCR), we measured concentrations of human adenovirus group F, enteroviruses, norovirus genogroups I and II, and rotavirus nucleic acids in wastewater solids two times per week for 26 months (n = 459 samples) between February 2021 and mid-April 2023. A novel probe-based PCR assay was developed and validated for adenovirus. We compared viral nucleic acid concentrations to positivity rates for viral infections from clinical specimens submitted to a local clinical laboratory to assess concordance between the data sets. We detected all viral targets in wastewater solids. At both wastewater treatment plants, human adenovirus group F and norovirus GII nucleic acids were detected at the highest concentrations (median concentrations greater than 105 copies/g), while rotavirus RNA was detected at the lowest concentrations (median on the order of 103 copies/g). Rotavirus, adenovirus group F, and norovirus nucleic acid concentrations were positively associated with clinical specimen positivity rates. Concentrations of tested viral nucleic acids exhibited complex associations with SARS-CoV-2 and other respiratory viral nucleic acids in wastewater, suggesting divergent transmission patterns.IMPORTANCEThis study provides evidence for the use of wastewater solids for the sensitive detection of enteric virus targets in wastewater-based epidemiology programs aimed to better understand the spread of enteric disease at a localized, community level without limitations associated with testing many individuals. Wastewater data can inform clinical, public health, and individual decision-making aimed to reduce the transmission of enteric disease.

Enteroviruses are major etiological agents of aseptic meningitis globally, however information on circulating enterovirus types associated with this disease in Wuxi, China is limited. In this study, cerebrospinal fluid samples were collected from 20 pediatric aseptic meningitis cases in a Wuxi hospital in 2020 and subjected to metagenomic analysis to detect pathogens. Enterovirus B was detected in 9 cases, including 7 echovirus 18 (E18) and 2 echovirus 11 (E11) strains. The E18 strains exhibited 87.5–98.2% nucleotide identity and phylogenetically clustered with other China E18 strains, while the E11 strains showed 97.59% identity and clustered within the D5 subgroup along with other China E11 strains. One E18 strain was identified as a novel recombinants with a distinct recombination breakpoint within 3D gene. These findings expand knowledge on enteroviruses associated with pediatric aseptic meningitis in Wuxi, and highlight the circulation of genetically diverse E18 and E11 strains, including novel E18 recombinants. Characterization of enterovirus diversity by metagenomic analysis is important for molecular diagnosis and epidemiological tracking of aseptic meningitis cases. Continued surveillance of circulating enterovirus strains in Wuxi that may cause future outbreaks is warranted.

Abstract Background The prevalence of respiratory viruses in children changed under strict infection control measures during the coronavirus disease 2019 (COVID-19) outbreak. In this study, we investigated the frequency of viral detection in the nasopharynx of paediatric patients with asthma exacerbations requiring hospitalization during the COVID-19 pandemic, as well as the distribution of causative viruses. Methods We included paediatric patients admitted for asthma exacerbations between November 2020 and December 2022 at a single centre in Kobe, Japan. Demographic, clinical, and laboratory data were collected from their medical records and using additional questionnaires. All patients enrolled in this study met the diagnostic criteria for asthma exacerbations outlined in the Japanese Pediatric Guideline for the Treatment and Management of Bronchial Asthma 2020. Statistical differences were calculated using univariate analyses (chi-square or Mann‒Whitney U test). Results We enrolled 203 children hospitalized for asthma attacks and collected nasopharyngeal samples from 189 patients. The median patient age was 3.0 years. Asthma severity was classified as mild (4.0%), moderate (82.3%), or severe (13.8%). The proportion of viral respiratory infections was 95.2% (180/189). The rate of patients with multiple viral infections was 20.6% (39/189). The most frequently detected pathogens were rhinovirus and enterovirus (RV/EV) at 69.3% (131/189), allowing for duplicate detection, followed by respiratory syncytial virus (RSV) at 28.6% (54/189). We also detected RV/EV almost every month compared to RSV and other viruses. In addition, RV/EV-positive patients were significantly older (p = 0.033), exhibited higher WBC counts (p

Abstract Background Parvoviruses are icosahedral, nonenveloped viruses with single-stranded DNA genomes of approximately 5 kb in length. In recent years, parvoviruses have frequently mutated and expanded their host range to cause disease in many wild animals by altering their tissue tropism. Animal infection mainly results in acute enteritis and inflammation of other organs. In this study, we used a viral metagenomic method to detect a novel parvovirus species in a red-crowned crane that died due to severe diarrhea in China. Results The presence of the viral genome in the kidney, lung, heart, liver, and intestine were confirmed by PCR. Histopathological examination of the intestine showed a large number of infiltrated inflammatory cells. The JL21/10 strain of the red-crowned crane parvovirus was first isolated from the intestine. Whole-genome sequence analysis showed that JL21/10 shared high identity with the red-crowned crane Parvovirinae strains yc-8 at the nucleotide level (96.61%). Phylogenetic analysis of the complete genome and NS1 gene revealed that the JL21/10 strain clustered with strains in chicken and revealed a close genetic relationship with the red-crowned crane parvovirus strains.The complete of VP2 gene analysis showed that JL21/10 shared identity with the red-crowned crane yc-8 strains (97.7%), chicken (55.4%),ducks(31.0%) and geese(30.1%) at the amino acid level. The result showed that red-crowned crane parvovirus may be cross-species transmission to chicken. However, There is little possibility of transmission to ducks and geese. Conclusion This is the first isolation and identification of a parvovirus in red-crowned crane that was associated with severe diarrhea.

Abstract Objectives This study aims to investigate molecular epidemiology and clinical characteristics of enterovirus associated hand-foot-mouth disease (HFMD) in Chengdu, China, 2013–2022. Monitoring the molecular epidemiology and clinical features of HFMD for up to 10 years may provide some ideas for future protection and control measures. Methods We conducted a retrospective analysis of the medical records of all patients with laboratory-confirmed HFMD-related enterovirus infection at the West China Second University Hospital from January 2013 to December 2022. We described the characteristics in serotype, age, sex distribution and hospitalization of enterovirus infection cases using data analysis and graphic description. Results A total of 29,861 laboratory-confirmed cases of HFMD-related enterovirus infection were reported from 2013 to 2022. There was a significant reduction in the number and proportion of EV-A71 cases after 2016, from 1713 cases (13.60%) in 2013–2015 to 150 cases (1.83%) in 2017–2019. During the COVID-19 pandemic, EV-A71 cases even disappeared. The proportion of CV-A16 cases decreased from 13.96% in 2013–2015 to 10.84% in 2017–2019 and then to 4.54% in 2020–2022. Other (non-EV-A71 and non-CV-A16) serotypes accounted for 95.45% during 2020–2022, with CV-A6 accounting for 50.39% and CV-A10 accounting for 10.81%. Thus, CV-A6 and CV-A10 became the main prevalent serotypes. Furthermore, There was no significant difference in the enterovirus prevalence rate between males and females. The hospitalization rate of EV-A71 patients was higher that of other serotypes. In general, the proportion of HFMD hospitalizations caused by other pathogens except for EV-A71, CV-A16, CV-A10 and CV-A16 was second only to that caused by EV-A71. The proportion of children over 4 years old infected with enterovirus increased. Conclusion The incidence of HFMD associated with enterovirus infection has decreased significantly and CV-A6 has been the main pathogen of HFMD in Chengdu area in recent years. The potential for additional hospitalizations for other untested enterovirus serotypes suggested that attention should also be paid to the harms of infections with unknown enterovirus serotypes. Children with HFMD were older. The development of new diagnostic reagents and vaccines may play an important role in the prevention and control of enterovirus infection.

Introduction: Acute Respiratory Infections (ARIs) are considered one of the leading causes of morbidity and mortality worldwide. Children under five and older adults are most likely to die from this cause. Objective: To describe the behavior of infection by respiratory viruses other than SARS-CoV-2 during the pandemic in a clinic in the Colombian Caribbean. Methods: This descriptive and retrospective study evaluates the characteristics, associated comorbidities, and requirements of hospitalization or Intensive Care Unit in patients diagnosed with respiratory viral infections treated at IMAT Oncomedica clinic from July 2020 to August 2022. Results: This study evaluated 351 patients with respiratory symptoms, observing an exponential increase in cases of respiratory infection as of April 2022, with a high proportion of syncytial virus infections mainly in children under 18 years of age (22.1%) and Human Rhinovirus/Enterovirus in patients with solid tumors and hematological disorders (48.8%), the latter was associated with a higher rate of hospitalization and ICU requirement in the individuals evaluated. Conclusions: Respiratory viruses other than SARS-CoV-2, such as Rhino/Enterovirus, RSV, and adenovirus, are circulating in the population at a clinic on the Colombian Caribbean coast. The findings should motivate public health authorities to conduct more thorough surveillance in the rest of the state.

Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 Å cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, including the substrate-binding surface within the SET domain. Structure-function analysis revealed that mutations of key residues in the SET domain resulted in severely reduced binding to 2A and complete protection from enteroviral infection. Our findings provide insight into the molecular basis of the SETD3-2A interaction and a framework for the rational design of host-directed therapeutics against enteroviruses.

Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease in infants and children with potential for fatal complications such as encephalitis and acute flaccid myelitis. This study examined the long-term immunity conferred by EV71vac, an inactivated EV-A71 vaccine adjuvanted with aluminum phosphate, in children from the age of 2 months to

Enterovirus-D68 (EV-D68) is a reemerging virus that has been associated with numerous outbreaks in children in the past 10 years. Most assays examining viral infection kinetics have relied on the use of quantitative RT-PCR (qRT-PCR) assays as an assay of choice. Though valuable, there are inherent limitations that introduce variability, thereby reducing its value when comparing results across the field. Unlike the qRT-PCR assay that uses a standard curve to determine the copy number of viral RNA, the droplet digital PCR assay (ddPCR) directly quantifies the absolute number of copies within a given sample, which in turn makes the assay highly sensitive and accurate. Here, we have developed an EV-D68-specific ddPCR assay that effectively quantifies EV-D68 RNA copies in both cells and supernatants within a dynamic range of 6.7 × 10−3 copies/μL to 1.2 × 104 copies/μL of the sample. The assay was highly specific for a broad range of EV-D68 isolates (Fermon, US/MO/14-18947, US/MO/14-18949, US/KY/14-18953, USA/2018-23088, USA/2020-23336 and EV-D68-infected human nasal turbinate samples from the 2022 outbreak) without cross-reactivity to other viruses such as Enterovirus-A71 (EV-A71), Human Parechovirus (HPeV)-1 and -2, Coxsackievirus (CV)-B1, Human Coronavirus (HCoV)-NL63, SARS-CoV-2, Influenza-A and B, Rhinovirus, and Respiratory Syncytial Virus (RSV)-A2, which are known to cause infection in children. The assay was able to readily quantify EV-D68 in infected cells and supernatants along with nasal turbinate samples collected from children during the 2022 outbreak. Our results suggest that the assay can be readily translated to accurately quantify viral loads in tissues and body fluids such as plasma and lung or nasal aspirates.

Enteroviruses are RNA viruses that initiate infections through the gastrointestinal (GI) tract and are associated with enteric illness in individuals of all ages. Most serious infections of enteroviruses are in infants and young children where it is the common cause of aseptic meningitis and other systemic diseases, leading to a high mortality rate. Enteroviruses belong to the small non-enveloped family of the Picornaviridae family. The virus can spread mainly through fecal–oral and respiratory routes. In the Arabian Gulf countries, the incidence of enteroviral infections is only restricted to a few reports, and thus, knowledge of the epidemiology, characteristics, and pathogenesis of the virus in the gulf countries remains scarce. In this minireview, we sought to provide an overview of the characteristics of enterovirus and its pathogenesis, in addition to gathering the reports of enterovirus infection prevalence in Gulf Cooperation Council (GCC) countries. We also present a summary of the common methods used in its detection.

Enteroviruses (EVs) are well-known causes of a wide range of infectious diseases in infants and young children, ranging from mild illnesses to severe conditions, depending on the virus genotypes and the host’s immunity. Recent advances in molecular surveillance and genotyping tools have identified over 116 different human EV genotypes from various types of clinical samples. However, the current knowledge about most of these genotypes, except for those of well-known genotypes like EV-A71 and EV-D68, is still limited due to a lack of comprehensive EV surveillance systems. This limited information makes it difficult to understand the true burden of EV-related diseases globally. Furthermore, the specific EV genotype associated with diseases varies according to country, population group, and study period. The same genotype can exhibit different epidemiological features in different areas. By integrating the data from established EV surveillance systems in the USA, Europe, Japan, and China, in combination with other EV infection studies, we can elaborate a better understanding of the distribution of prevalent EV genotypes and the diseases associated with EV. This review analyzed the data from various EV surveillance databases and explored the EV seroprevalence and the association of specific EV genotypes with human diseases.

Enterovirus genomic replication initiates at a predicted RNA cloverleaf (5′CL) at the 5′ end of the RNA genome. The 5′CL contains one stem (SA) and three stem-loops (SLB, SLC, SLD). Here, we present an analysis of 5′CL conservation and divergence for 209 human health-related serotypes from the enterovirus genus, including enterovirus and rhinovirus species. Phylogenetic analysis indicates six distinct 5′CL serotypes that only partially correlate with the species definition. Additional findings include that 5′CL sequence conservation is higher between the EV species than between the RV species, the 5′CL of EVA and EVB are nearly identical, and RVC has the lowest 5′CL conservation. Regions of high conservation throughout all species include SA and the loop and nearby bases of SLB, which is consistent with known protein interactions at these sites. In addition to the known protein binding site for the Poly-C binding protein in the loop of SLB, other conserved consecutive cytosines in the stems of SLB and SLC provide additional potential interaction sites that have not yet been explored. Other sites of conservation, including the predicted bulge of SLD and other conserved stem, loop, and junction regions, are more difficult to explain and suggest additional interactions or structural requirements that are not yet fully understood. This more intricate understanding of sequence and structure conservation and variability in the 5′CL may assist in the development of broad-spectrum antivirals against a wide range of enteroviruses, while better defining the range of virus isotypes expected to be affected by a particular antiviral.

After the first phase of the COVID-19 pandemic in Europe, a new highly pathogenic variant of echovirus 11 (E11) was detected. The aim of this study was to analyze the genetic diversity of Polish E11 environmental and clinical strains circulating between 2017 and 2023 as well as compare them with E11 strains isolated from severe neonatal sepsis cases reported in Europe between 2022 and 2023. Additionally, the study explores the effectiveness of environmental monitoring in tracking the spread of new variants. For this purpose, the complete sequences of the VP1 capsid protein gene were determined for 266 E11 strains isolated in Poland from 2017 to 2023, and phylogenetic analysis was performed. In the years 2017–2023, a significant increase in the detection of E11 strains was observed in both environmental and clinical samples in Poland. The Polish E11 strains represented three different genotypes, C3, D5 and E, and were characterized by a high diversity. In Poland, the intensive circulation of the new variant E11, responsible for severe neonatal infections with a high mortality in Europe, was detected in the years 2022–2023. This investigation demonstrates the important role of environmental surveillance in the tracking of enteroviruses circulation, especially in settings with limited clinical surveillance.

Enteroviruses (EVs) are ubiquitous viruses that circulate worldwide, causing sporadic or epidemic infections, typically during the summer and fall. They cause a broad spectrum of illnesses, ranging from an unspecified febrile clinical presentation to a severe illness. EVs are recognized to be the most frequent etiological agents of aseptic meningitis in children. However, as the infection is usually mild and self-limiting, it remains underestimated, and the epidemiology of EVs is poorly understood. To date, no vaccine or effective therapy for all types of enteroviruses is available, and EVs constitute a public health concern. Here, we investigated the molecular epidemiology of EV strains circulating in the Lazio region over a 10-year time span (2012–2023) by using a sequence-typing approach and phylogenetic analysis. The epidemiological trend of EV infection has undergone changes during the SARS-CoV-2 pandemic (2020–2021), which resulted in a modification in terms of the number of diagnosed cases and seasonality. From 2022, the circulation of EVs showed a behavior typical of the pre-pandemic period, although changes in predominantly circulating strains have been noted. Both epidemic and sporadic circulation events have been characterized in the Lazio region. Further analyses are needed to better characterize any strain with higher potential pathogenic power and to identify possible recombinant strains.

The open-source drug library, namely, MMV Pandemic Response Box, contains 153 antiviral agents, a chemically and pharmacologically diverse mixture of early-stage, emerging anti-infective scaffolds, and mature compounds currently undergoing clinical development. Hence, the Pandemic Response Box might contain compounds that bind and interfere with target molecules or cellular pathways that are conserved or shared among the closely related viruses with enterovirus A71 (EV-A71). This study aimed to screen antiviral agents included in the Pandemic Response Box for repurposing to anti-EV-A71 activity and investigate the inhibitory effects of the compounds on viral replication. The compounds’ cytotoxicity and ability to rescue infected cells were determined by % cell survival using an SRB assay. The hit compounds were verified for anti-EV-A71 activity by virus reduction assays for viral RNA copy numbers, viral protein synthesis, and mature particle production using qRT-PCR, Western blot analysis, and CCID50 assay, respectively. It was found that some of the hit compounds could reduce EV-A71 genome replication and protein synthesis. D-D7 (2-pyridone-containing human rhinovirus 3C protease inhibitor) exhibited the highest anti-EV-A71 activity. Even though D-D7 has been originally indicated as a polyprotein processing inhibitor of human rhinovirus 3C protease, it could be repurposed as an anti-EV-A71 agent.

Human enterovirus (EV) infections can lead to various manifestations, with variable correlations between genotypes and symptoms. Human enterovirus D68 (EV-D68) was considered to be associated with acute respiratory disease and acute flaccid myelitis. In this short report, both EV-D68 and poliovirus 3 were detected in the stool of a hospitalized 5-month child who presented with acute respiratory symptoms and who was recently vaccinated with oral polio vaccine (OPV), using a metatranscriptomic high-throughput sequencing method. The nearly full-length genome sequences with complete open reading frames of EV-D68 and poliovirus 3 were assembled. One previously-reported neurovirulence-related amino acid substitution (T860N) in the EV-D68 VP1 region was observed, but the patient showed no neurological symptoms. More attention should be paid to EV-D68, and continuous multiple syndrome-based surveillance on non-polio enterovirus is called for.

Enteroviruses (EVs) are classified into 15 species according to their sequence diversity. They include four human EV (A, B, C, and D) and three rhinoviruses (A, B, and C), and cause diseases in millions of people worldwide. Generally, individuals with enteroviral infections have mild clinical symptoms, including respiratory illness, vomiting, diarrhea, dizziness, and fever. More importantly, some members of the human EV family are neurotropic pathogens that may cause a wide range of clinical diseases, such as aseptic meningitis and encephalitis. Previously, the EV that caused the most severe neurotropic symptoms was poliovirus (PV), a member of the EV C group. Poliovirus has been eliminated in most countries through a global vaccination campaign. Non-PV EVs infect the central nervous system (CNS) and are the major EVs causing neurological diseases. These human non-PV EVs include EV A (e.g., EV-A71, CVA6, and CVA16), B (e.g., CVA9 and CVB3, CVB5, echovirus 11 [E11], E30, and E7), C (e.g., CVA24), and D (e.g., EV-D68). Here, we review the relationship between EV infection and CNS diseases and advance in the use of cellular receptors and host immune responses during viral infection.

Background: Maternal transplacental antibody is an important origins of passive immunity against neonatal enterovirus infection. Echovirus 11 (E11) and coxsackievirus B3 (CVB3) are important types causing neonatal infections. There were few investigations of enterovirus D68 (EVD68) infection in neonates. We aimed to investigate the serostatus of cord blood for these three enteroviruses and evaluate the factors associated with seropositivity. Methods: We enrolled 222 parturient (gestational age 34–42 weeks) women aged 20–46 years old between January and October 2021. All participants underwent questionnaire investigation and we collected the cord blood to measure the neutralization antibodies against E11, CVB3 and EVD68. Results: The cord blood seropositive rates were 18% (41/222), 60% (134/232) and 95% (211/222) for E11, CVB3 and EVD68, respectively (p

Acute gastroenteritis (AGE) has a major impact on morbidity and mortality worldwide. The viral aetiology of diarrhoeal diseases may remain unknown due to limited diagnostic facilities. Non-polio enteroviruses (NPEVs) are the third most frequent pathogen detected in stool specimens from AGE cases, yet their potential role in AGE is uncertain. In Nepal, limited data are available on NPEVs, due to both the lack of an adequate surveillance program and the availability of tests. The global polio eradication initiative effort of the WHO has eradicated the incidence of poliomyelitis and acute flaccid paralysis (AFP) from many parts of the world, including Nepal. However, cases of AFP associated with NPEVs have been reported in different countries, including the neighbouring India. This study aims to investigate the diarrhoeal stool samples from a birth cohort until the age of 36 months for NPEVs and the genotype diversity of NPEV in community children with diarrhoea. A total of 280 longitudinal diarrhoeal stool samples that were negative for other enteric pathogens were tested using RT-PCRs. NPEVs was detected in 97 stool specimens (34.6%) and were significantly more frequent in infants up to one year of age. This study identified 17 various NPEV types, with the dominating species being Enterovirus B (EV-B). Ten different types of echoviruses were recorded in this study, with the two rare NPEVs B74 and A120. Based on prevalence, seasonality, and diversity, further studies are warranted to investigate the role of enterovirus in diarrhoeal disease.

This study aimed to compare the sensitivity of two-phase separation and the filtration method using a mixed cellulose ester (MCE) membrane to detect enteroviruses in sewage samples. From December 2015 to July 2016, four domestic sewage samples (1 L/sample) were collected monthly from the Guangzhou Liede Sewage Treatment Plant, and each sewage sample was divided into two aliquots (500 mL). The sewage sample was concentrated using the two-phase separation and the filtration method using an MCE membrane, and the treated solutions were inoculated into cells for enterovirus isolation. Polymerase chain reaction amplification, VP1 sequencing, and enterovirus molecular typing were performed on the positive isolates. The detection rates of poliovirus (PV) and non-polio enterovirus (NPEV) obtained using the filtration method using an MCE membrane were higher than those using the two-phase separation method. McNemar's test showed that the detection rates of PV, NPEV, type 1 Sabin-like (SL1), type 2 Sabin-like (SL2), and type 3 Sabin-like (SL3) strain were not statistically significant (P > 0.05). In Guangdong Province, China, the detection rates for PV and NPEV were 53.13% and 62.50% (20/32), respectively. Twenty-seven PVs were isolated, three highly variable strains of the type 1 vaccine, with seven nucleotide substitutions in the VP1 region, compared with the type 1 Sabin strains. Eighty-seven strains of NPEV were isolated and nine serotypes were identified, among which coxsackievirus B3 (CVB3), echovirus 6(E6), and echovirus 11(E11) were the dominant strains. The filtration method using an MCE membrane is more sensitive than two-phase separation and can be used as a robust, sensitive, and cost-effective method to isolate enteroviruses from sewage.

We observed an intense enterovirus D68 outbreak in children in southwest Finland in August–September 2022. We confirmed enterovirus D68 infection in 56 children hospitalized for respiratory illnesses and in 1 child with encephalitis but were not able to test all suspected patients. Continuing surveillance for enterovirus D68 is needed.

ABSTRACT Enterovirus D68 (EV-D68) is predominantly associated with mild respiratory infections, but can also cause severe respiratory disease and extra-respiratory complications, including acute flaccid myelitis. Systemic dissemination of EV-D68 is crucial for the development of extra-respiratory diseases, but it is currently unclear how EV-D68 spreads systemically (viremia). We hypothesize that immune cells contribute to the systemic dissemination of EV-D68, as this is a mechanism commonly used by other enteroviruses. Therefore, we investigated the susceptibility and permissiveness of human primary immune cells for different EV-D68 isolates. In human peripheral blood mononuclear cells inoculated with EV-D68, only B cells were susceptible but virus replication was limited. However, in B cell-rich cultures, such as Epstein–Barr virus-transformed B-lymphoblastoid cell line (BLCL) and primary lentivirus-transduced B cells, which better represent lymphoid B cells, were productively infected. Subsequently, we showed that dendritic cells (DCs), particularly immature DCs, are susceptible and permissive for EV-D68 infection and that they can spread EV-D68 to autologous BLCL. Altogether, our findings suggest that immune cells, especially B cells and DCs, could play an important role in the pathogenesis of EV-D68 infection. Infection of these cells may contribute to systemic dissemination of EV-D68, which is an essential step toward the development of extra-respiratory complications.IMPORTANCEEnterovirus D68 (EV-D68) is an emerging respiratory virus that has caused outbreaks worldwide since 2014. EV-D68 infects primarily respiratory epithelial cells resulting in mild respiratory diseases. However, EV-D68 infection is also associated with extra-respiratory complications, including polio-like paralysis. It is unclear how EV-D68 spreads systemically and infects other organs. We hypothesized that immune cells could play a role in the extra-respiratory spread of EV-D68. We showed that EV-D68 can infect and replicate in specific immune cells, that is, B cells and dendritic cells (DCs), and that virus could be transferred from DCs to B cells. Our data reveal a potential role of immune cells in the pathogenesis of EV-D68 infection. Intervention strategies that prevent EV-D68 infection of immune cells will therefore potentially prevent systemic spread of virus and thereby severe extra-respiratory complications.

BackgroundEnteroviruses (EV) constitute a diverse group of viruses manifesting a broad spectrum of clinical presentations in humans ranging from mild skin manifestations to more severe central nervous system (CNS) infection. Severe infections are reported with increased frequency globally, albeit the burden of diseases and the evolution of circulating viruses is largely unknown. We aimed to systematically explore contemporary trends in hospitalizations attributed to EV infections using national hospitalization discharge data.MethodsWe utilized the Danish National Patient Register which holds information on all contacts to Danish hospitals. We covered eight full years (2015-2022). Length-of-stay and administrative procedure codes were used to distinguish hospital admissions from outpatient visits. We utilized burden of disease estimates and distribution statistics.ResultsWe identified 1029 hospitalizations and 1970 outpatient visits due to EV infections. The hospital admissions were primarily associated with CNS-infections (n=570, 55.4%) and skin (n=252, 24.5%), with variation over the studied period. The admitted patients were predominately children (43.8%) though patients were identified in all ages. The clinical manifestation was associated with age, with CNS infections dominating in the neonates and adults, and skin infections dominating in children 1-2 years (17.2%). Outpatient visits were predominantly observed among children 1-2 years (55.0%), presenting with skin symptoms (77.9%). We show a seasonal pattern of EV infections with summer/fall peaks and markedly impact on the EV hospitalization burden related to COVID-19 mitigation measures including national lockdown periods. 25% of hospital admissions occurred during 2020-2022.ConclusionEV infections caused both hospital admissions and outpatient visits in the period studied, predominately among children aged 1-2 years. Overall, skin infections dominated the outpatient visits, while the majority of hospital admissions were due to CNS infections. The pandemic period did not change the seasonal pattern of EV infections but notably lowered the number of admissions to hospital with CNS infection and raised the number of outpatient admissions with skin infection.

The past decade has seen the global reemergence and rapid spread of enterovirus D68 (EV-D68), a respiratory pathogen that causes severe respiratory illness and paralysis in children. EV-D68 was first isolated in 1962 from children with pneumonia. Sporadic cases and small outbreaks have been reported since then with a major respiratory disease outbreak in 2014 associated with an increased number of children diagnosed with polio-like paralysis. From 2014-2018, major outbreaks were reported every other year in a biennial pattern with > 90% of the cases occurring in children under the age of 16. With the outbreak of SARS-CoV-2 and the subsequent COVID-19 pandemic, there was a significant decrease in the prevalence EV-D68 cases along with other respiratory diseases. However, since the relaxation of pandemic social distancing protocols and masking mandates the number of EV-D68 cases have begun to rise again-culminating in another outbreak in 2022. Here we review the virology, pathogenesis, and the immune response to EV-D68, and discuss the epidemiology of EV-D68 infections and the divergence of contemporary strains from historical strains. Finally, we highlight some of the key challenges in the field that remain to be addressed.

BackgroundEnteroviruses have the potential to cause both high morbidity and mortality especially in children. High season in Norway is between August and November, but this seasonality was interrupted by the COVID-19 pandemic.MethodsIn this study, we describe the enterovirus surveillance in Norway before and during the COVID-19 pandemic including the years from the start of 2016 until the end of 2022. Screening of enterovirus was performed by both laboratory developed methods and FilmArray® ME Panel. Relevant samples were typed, mostly by VP1 sequencing.ResultsSeventy-four percent of all cases occurred in infants under five years of age. A significant reduction in positive cases was observed during the peak years of the COVID-19 pandemic compared to the years before. Pre-pandemic, a wide range of types from all four enterovirus species were detected. During the years with COVID-19 infection control measures, significantly fewer enterovirus types were found along with a substantial reduction in the detection rate.ConclusionEnterovirus surveillance discovered a large amount of different types mainly affecting infants. The positivity rate was markedly reduced during the pandemic in 2020-2022 and fewer types occurred.

Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of anti-viral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-and-run scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies.

Introduction: Conjunctivitis is a highly prevalent ocular disease that flares up every year. The humidity and high temperature favour the causative agents responsible for the epidemic. Acute infective conjunctivitis may be either viral or bacterial, a distinct type of condition with unique clinical features and treatment approaches. The aim of the study was to find out the prevalence of acute conjunctivitis among patients visiting the outpatient Department of Ophthalmology in a tertiary care centre. Methods: This descriptive cross-sectional study was conducted among the patients visiting the outpatient Department of Ophthalmology. Data of 30 August 2023 to 30 September 2023 was collected between 21 November 2023 to 24 November 2023. All patients presenting in the Ophthalmology Department having complete hospital record were included in the study. Patients having missing data on the medical records of the hospital were excluded. A convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Results: Among 5,507 patients, acute conjunctivitis was seen in 1240 (22.52%) (21.42-23.62, 95% Confidence Interval). The majority were male 732 (59.03%) and adults 760 (61.29%) with a mean age of 32.56±18.74 years. Conclusions: The prevalence of conjunctivitis among patients visiting the outpatient Department of Opthalmology was found to be higher than other studies done in similar settings.

ABSTRACTEnterovirus D68 (EV-D68) contributes significantly to pathogen-induced respiratory illnesses and severe neurological disorders like acute flaccid myelitis. We lack EV-D68 preventive measures, and knowledge of its molecular and cellular biology is incomplete. Multiple studies have highlighted the role of membrane compartments and autophagy during picornavirus multiplication. Galitska et al. found that EV-D68 also exploits cellular autophagic compartments and relies on autophagic machinery as pro-viral factors (G. Galitska, A. Jassey, M. A. Wagner, N. Pollack, et al., mBio e02141-23, 2023, https://doi.org/10.1128/mbio.02141-23). Surprisingly, failure of the autophagic compartment to acidify early during EV-D68 infection causes a delay in RNA synthesis that has not been reported for other enteroviruses. This delay appears to reflect the inability of viral proteins 2B and 3A to engage membranes stably, leading to their degradation in the cytoplasm. Observations like this underscore the importance of studying individual members of the virus genus. It will be interesting to understand how this phenomenon connects to EV-D68 pathogenesis, if at all.