Global prevalence and case fatality rate of Enterovirus D68 infections, a systematic review and meta-analysis.

A substantial amount of epidemiological data has been reported on Enterovirus D68 (EV-D68) infections after the 2014 outbreak. Our goal was to map the case fatality rate (CFR) and prevalence of current and past EV-D68 infections. We conducted a systematic review (PROSPERO, CRD42021229255) with published articles on EV-68 infections in PubMed, Embase, Web of Science and Global Index Medicus up to January 2021. We determined prevalences using a model random effect. Of the 4,329 articles retrieved from the databases, 89 studies that met the inclusion criteria were from 39 different countries with apparently healthy individuals and patients with acute respiratory infections, acute flaccid myelitis and asthma-related diseases. The CFR estimate revealed occasional deaths (7/1353) related to EV-D68 infections in patients with severe acute respiratory infections. Analyses showed that the combined prevalence of current and past EV-D68 infections was 4% (95% CI = 3.1-5.0) and 66.3% (95% CI = 40.0-88.2), respectively. The highest prevalences were in hospital outbreaks, developed countries, children under 5, after 2014, and in patients with acute flaccid myelitis and asthma-related diseases. The present study shows sporadic deaths linked to severe respiratory EV-D68 infections. The study also highlights a low prevalence of current EV-D68 infections as opposed to the existence of EV-D68 antibodies in almost all participants of the included studies. These findings therefore highlight the need to implement and/or strengthen continuous surveillance of EV-D68 infections in hospitals and in the community for the anticipation of the response to future epidemics.

Timing of Endotracheal Intubation in Patients with Fulminant Enterovirus 71 Infection.

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.

Monoclonal antibody against EV71 3Dpol inhibits the polymerase activity of RdRp and virus replication.

BACKGROUND: Enterovirus A 71 (EV71) is a neurotropic virus that may lead to acute flaccid paralysis, encephalitis, cardiopulmonary failure or even death. No vaccine and defensive drug controlling EV71 is currently available, novel and efficient antiviral drug or vaccine is therefore urgently needed. 3Dpol (RNA-dependent RNA polymerase (RdRp)) has been an important target for anti-EV71 drug development. METHODS: A panel of monoclonal IgG antibodies (mAbs) against EV71 3Dpol were generated by traditional cell fusion methods. And the antibody affinity and specificity to EV71 3Dpol were evaluated by Enzyme-linked Immunosorbent Assay (ELISA), Indirect Fluorescent Assay (IFA) and Western blotting. Antiviral activities of these antibodies were also determined in vitro and in vivo. RESULTS: Two mAbs towards EV71 3Dpol were able to effectively suppress EV71 replication in Vero-1008 cell when intracellarly delivered. And they also dampened the RNA polymerase activity of 3Dpol in vitro. More importantly, these mAbs provided partial protection in EV71-challenged neonatal murine challenge model. CONCLUSIONS: These results showed that two of mAbs against EV71 3Dpol inhibited EV71 replication and could be utilized as promising therapeutic drug candidate.

Estimating the Severity Profile of Enterovirus A71 Infections in Children: A Bayesian Synthesis Framework.

Enterovirus A71 (EV-A71) is responsible for the majority of severe cases of hand, foot, and mouth disease, but little evidence is available on the severity profile of EV-A71 infections. We formulated a hierarchical Bayesian model that synthesized data on diseases/events associated with EV-A71 and EV-A71 antibody responses to infection among unvaccinated children from large clinical trials of EV-A71 vaccination, which were conducted in Jiangsu and Beijing during 2012 and 2013, to reconstruct the severity profile in a unified framework. On average, 15.1% of the children aged 6-35 months were infected by EV-A71 during 1-year follow-up in a mild epidemic season. We estimated that 9.7%, 2.2%, and 0.6% of children infected with EV-A71 were diagnosed with EV-A71-associated diseases, were hospitalized, and showed severe complications, respectively. We estimated on average 1 death per 10,000 EV-A71 infections for children aged 6-35 months. Approximately 70% of children had ≥4-fold rises in antibody titers after infection. Most EV-A71 infections in young children are mild, and overall 2.2% of the infected patients were hospitalized in the 2 trials. There remain several uncertainties about the immune response after infection and the duration of immunity against EV-A71 reinfection.

Flt3 ligand treatment reduces enterovirus A71 lethality in mice with enhanced B cell responses.

Enterovirus A71 (EV-A71) infection can induce encephalitis, which causes death or long-term neurological sequelae, especially in young children. Using a murine infection model, we searched for anti-EV-A71 agents, because effective therapies are not available to control fatal infection. In EV-A71-infected mice, treatment with the hematopoietic growth factor, Fms-like tyrosine-kinase 3 ligand (Flt3 ligand) before infection reduced the lethality and tissue viral loads. Flt3 ligand failed to enhance the production of type I interferons. Instead, Flt3 ligand boosted the numbers of dendritic cells and, particularly lymphocytes in infected organs with an expansion of spleen B cells, and resulted in an increased titer of virus-specific antibody with neutralizing activity in the serum. The protective effect of Flt3 ligand was abolished in B cell-deficient mice. Our findings revealed that Flt3 ligand administration promotes resistance to EV-A71 infection with enhanced B cell response in a mechanism rarely reported before.

Factors associated with fatal outcome of children with enterovirus A71 infection: a case series.

Enterovirus A-71 (EV-A71) may be fatal, but the natural history, symptoms, and signs are poorly understood. This study aimed to examine the natural history of fatal EV-A71 infection and to identify the symptoms and signs of early warning of deterioration. This was a clinical observational study of fatal cases of EV-A71 infection treated at five Chinese hospitals between 1 January 2010 and 31 December 2012. We recorded and analysed 91 manifestations of EV-A71 infection in order to identify early prognosis indicators. There were 54 fatal cases. Median age was 21.5 months (Q1-Q3: 12-36). The median duration from onset to death was 78.5 h (range, 6 to 432). The multilayer perceptron analysis showed that ataxia respiratory, ultrahyperpyrexia, excessive tachycardia, refractory shock, absent pharyngeal reflex, irregular respiratory rhythm, hyperventilation, deep coma, pulmonary oedema and/or haemorrhage, excessive hypertension, tachycardia, somnolence, CRT extension, fatigue or sleepiness and age were associated with death. Autopsy findings (n = 2) showed neuronal necrosis, softening, perivascular cuffing, colloid and neuronophagia phenomenon in the brainstem. The fatal cases of enterovirus A71 had neurologic involvement, even at the early stage. Direct virus invasion through the neural pathway and subsequent brainstem damage might explain the rapid progression to death.

A Mouse Model of Enterovirus D68 Infection for Assessment of the Efficacy of Inactivated Vaccine.

In recent years, enterovirus D68 (EVD68) has been reported increasingly to be associated with severe respiratory tract infections and acute flaccid myelitis (AFM) in children all over the world. Yet, no effective vaccines or antiviral drugs are currently available for EVD68. Although several experimental animal models have been developed, immunogenicity and protective efficacy of inactivated EVD68 vaccines has not been fully evaluated. To promote the development of vaccines, we established an Institute of Cancer Research (ICR) suckling mouse model of EVD68 infection in this study. The results showed that ICR neonatal mice up to about nine days of age were susceptible to infection with EVD68 clinical strain US/MO/14-18947 by intraperitoneal injection. The infected mice exhibited progressive limb paralysis prior to death and the mortality of mice was age- and virus dose-dependent. Tissue viral load analysis showed that limb muscle and spinal cord were the major sites of viral replication. Moreover, histopathologic examination revealed the severe necrosis of the limb and juxtaspinal muscles, suggesting that US/MO/14-18947 has a strong tropism toward muscle tissues. Additionally, ß-propiolactone-inactivated EVD68 vaccine showed high purity and quality and induced robust EVD68-specific neutralizing antibody responses in adult mice. Importantly, results from both antisera transfer and maternal immunization experiments clearly showed that inactivated EVD68 vaccine was able to protect against lethal viral infection in the mouse model. In short, these results demonstrate the successful establishment of the mouse model of EVD68 infection for evaluating candidate vaccines against EVD68 and also provide important information for the development of inactivated virus-based EVD68 vaccines.

First Report of a Fatal Case Associated with EV-D68 Infection in Hong Kong and Emergence of an Interclade Recombinant in China Revealed by Genome Analysis.

A fatal case associated with enterovirus D68 (EV-D68) infection affecting a 10-year-old boy was reported in Hong Kong in 2014. To examine if a new strain has emerged in Hong Kong, we sequenced the partial genome of the EV-D68 strain identified from the fatal case and the complete VP1, and partial 5'UTR and 2C sequences of nine additional EV-D68 strains isolated from patients in Hong Kong. Sequence analysis indicated that a cluster of strains including the previously recognized A2 strains should belong to a separate clade, clade D, which is further divided into subclades D1 and D2. Among the 10 EV-D68 strains, 7 (including the fatal case) belonged to the previously described, newly emerged subclade B3, 2 belonged to subclade B1, and 1 belonged to subclade D1. Three EV-D68 strains, each from subclades B1, B3, and D1, were selected for complete genome sequencing and recombination analysis. While no evidence of recombination was noted among local strains, interclade recombination was identified in subclade D2 strains detected in mainland China in 2008 with VP2 acquired from clade A. This study supports the reclassification of subclade A2 into clade D1, and demonstrates interclade recombination between clades A and D2 in EV-D68 strains from China.

Evolución fatal por enterovirus A71 / Fatal evolution by enterovirus A71

El enterovirus (EV) A71 es un serotipo de EV aislado, hasta ahora, frecuentemente en infecciones banales en nuestro medio (síndrome febril, enfermedad mano-pie-boca, herpangina...). No era muy frecuente en nuestro país hasta el año 2012 cuando triplicó su incidencia. Últimamente se ha aislado asociando clínica neurológica grave, miocarditis o edema de pulmón y puntualmente exitus lo que ha provocado una alarma social generalizada (AU)

The enterovirus (EV) A71 is a serotype of EV isolated, until now, frequently in banal infections in our environment (febrile syndrome, hand foot mouth disease, herpangina...). It was not very frequent in our country until 2012 when its incidence tripled. Lately it has been isolated associating severe neurological clinic, myocarditis or pulmonary edema and punctually exitus which has provoked a widespread social alarm (AU)

Clinical manifestations of severe enterovirus 71 infection and early assessment in a Southern China population.

BACKGROUND: Enterovirus 71 (EV-A71) shows a potential of rapid death, but the natural history of the infection is poorly known. This study aimed to examine the natural history of EV-A71 infection. METHODS: This was a prospective longitudinal observational study performed between January 1st and October 31st, 2012, at three hospitals in Guangdong, China. Subjects with positive EV-A71 RNA laboratory test results were included. Disease progression was documented with MRI, autopsies, and follow-up. Symptoms/signs with potential association with risk of death were analyzed. RESULTS: Among the 288 patients, neurologic symptoms and signs were observed (emotional movement disorders, dyskinesia, involuntary movements, autonomic dysfunction, and disturbance of consciousness). Some of them occurred as initial symptoms. Myoclonic jerks/tremors were observed among >50% of the patients; nearly 40% of patients presented fatigue and 25% were with vomiting. Twenty-eight patients (9.7%) presented poor peripheral perfusion within 53.4 ± 26.1 h; 23 patients (8.0%) presented pulmonary edema and/or hemorrhage within 62.9 ± 28.6 h. Seventeen (5.9%) patients were in a coma. Seven (2.4%) patients died within 62.9 ± 28.6 h. Seventy-seven survivors underwent head and spinal cord MRI and 37.7% (29/77) showed abnormalities. Two fatal cases showed neuronal necrosis, softening, perivascular cuffing, colloid, and neuronophagia phenomenon in the brainstem. CONCLUSIONS: Patients with EV-A71 infection showed high complexity of symptoms and onset timing. Death risk may be indicated by autokinetic eyeball, eyeball ataxia, severe coma, respiratory rhythm abnormality, absent pharyngeal reflex, ultrahyperpyrexia, excessive tachycardia, pulmonary edema and/or hemorrhage, and refractory shock and ataxic respiration. Early assessment of these symptoms/signs is important for proper management.

ROLE OF VIRAL PATHOGENS IN INFANTS WITH SYSTEMIC INFECTION AT THE NEWBORN INTENSIVE CARE UNITS IN GEORGIA.

In Georgia, causative agents among infants with systemic infections are generally not identified and "neonatal sepsis" is usually diagnosed and treated without determining the etiology. The objective of this study was to estimate the role of viral pathogens (Herpesviridae and Enteroviruses) among neonates with generalized infections. A cross-sectional study was performed among neonates younger than <8 weeks admitted to a neonatal intensive care unit (NICU) at the two largest pediatric hospitals in Tbilisi, Georgia. Laboratory tests were performed by consensus and then by type-specific PCR methods. A total of 187 infants were recruited from the NICUs; most participants (74.9%) were of normal birth weight at admission to the NICU and half (51.3%) were younger than 7 days of age. Almost all babies (91.4%) were treated with a broad-spectrum antibiotic despite a lack of microbe identification. While the overall mortality rate of infants with a systemic infection was 21.9 %, neonatal outcomes were more favorable when the infection was due to enteroviruses (2.9% mortality rate) compared to a herpesvirus infection (16.1% mortality rate). Multivariate analyses identified independent predictors associated with neonatal mortality. These included etiology of infection, APGAR score and the type of delivery. Our investigation suggests that viral pathogens play a substantial role in systemic infections among NICU infants. Utilizing molecular-based testing in these cases could improve both the clinical management and outcomes of neonates with generalized infections.

A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema.

Enterovirus 71 (EV-A71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. Animal models of EV-A71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. Specifically, neurogenic pulmonary oedema (NPE)-the main cause of EV-A71 infection-related mortality-is not observed in any of these models. This limits their utility in understanding viral pathogenesis of neurologic infections. We report the development of a mouse model of EV-A71 infection displaying NPE in severely affected animals. We inoculated one-week-old BALB/c mice with an adapted EV-A71 strain and identified clinical signs consistent with observations in human cases and other animal models. We also observed respiratory distress in some mice. At necropsy, we found their lungs to be heavier and incompletely collapsed compared to other mice. Serum levels of catecholamines and histopathology of lung and brain tissues of these mice strongly indicated onset of NPE. The localization of virally-induced brain lesions also suggested a potential pathogenic mechanism for EV-A71-induced NPE. This novel mouse model of virally-induced NPE represents a valuable resource for studying viral mechanisms of neuro-pathogenesis and pre-clinical testing of potential therapeutics and prophylactics against EV-A71-related neurologic complications.

A monoclonal antibody to ameliorate central nervous system infection and improve survival in a murine model of human Enterovirus-A71 encephalomyelitis.

BACKGROUND: Enterovirus A71 (EV-A71) encephalomyelitis is an often fatal disease for which there is no specific treatment available. Passive immunization with a specific monoclonal antibody to EV-A71 was used on a murine model of EV-A71 encephalomyelitis to evaluate its therapeutic effectiveness before and after established central nervous system (CNS) infection. METHODS: Mice were intraperitoneally-infected with a mouse-adapted EV-A71 strain and treated with a dose of monoclonal antibody (MAb) daily for 3 days on day 1, 2 and 3 post-infection or for 3 days on 3, 4 and 5 post-infection. Treatment effectiveness was evaluated by signs of infection and survival rate. Histopathology and qPCR analyses were performed on mice sacrificed a day after completing treatment. RESULTS: In mock-treated mice, CNS infection was established from day 3 post-infection. All mice treated before established CNS infection, survived and recovered completely without CNS infection. All mice treated after established CNS infection survived with mild paralysis, and viral load and antigens/RNA at day 6 post-infection were significantly reduced. CONCLUSIONS: Passive immunization with our MAb could prevent CNS infection in mice if given early before the establishment of CNS infection. It could also ameliorate established CNS infection if optimal and repeated doses were given.

2014 outbreak of enterovirus D68 in North America.

Enterovirus D68 (EV-D68) is an emerging picornavirus which causes severe respiratory disease, predominantly in children. In 2014, the largest and most widespread outbreak of EV-D68 described to date was reported in North America. Hospitals throughout the United States and Canada reported surges in patient volumes and resource utilization from August to October, 2014. In the US a total of 1,153 infections were confirmed in 49 states, although this is an underestimate of the likely millions of cases that occurred but were not tested. EV-D68 was detected in 14 patients who died; the role of the virus in these deaths is unknown. A possible association between EV-D68 and cases of acute flaccid paralysis with spinal cord gray matter lesions, known as acute flaccid myelitis, was observed during the outbreak and is under investigation. The 2014 outbreak of EV-D68 in North America demonstrates the public health importance of this emerging pathogen.

Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration.

BACKGROUND: The benefits of intravenous immunoglobulin (IVIG) therapy for severe neonatal enterovirus infections are still controversial. OBJECT: To evaluate whether timing of IVIG administration might affect clinical outcomes of neonates with severe enteroviral infections. STUDY DESIGNS: We retrospectively analyzed 67 neonates with culture-confirmed severe enteroviral infection, defined as hepatitis with coagulopathy and thrombocytopenia. Clinical features, outcomes and the usage of IVIG therapy were collected and analyzed. IVIG administered within 3 days of illness onset was classified as early IVIG therapy. RESULTS: Of the 67 cases, 38 (57%) were male, 27 (40%) were premature, 57 (85%) had disease onset within 7 days of life and all but 2 cases were caused by coxsackievirus B group. Ten infants (15%) had clinically evident myocarditis. 41 infants (61%) received IVIG therapy and 29 were early IVIG therapy. Fifteen infants (22%) eventually died, without IVIG therapy for 7 infants. The deceased had a significantly higher peak serum aspartate aminotransferase (AST) level than the survivors (3539 vs. 866 IU/L, p<0.01). The timing of IVIG therapy was highly correlated with the timing of peak AST level in patients with early IVIG therapy. Multiple logistic regression analysis showed that a higher nadir hemoglobin level (adjusted odds ratio 2.8, 95% confidence interval: 1.4-5.4), no concurrent myocarditis (42.6 [3.4-5289]) and early IVIG therapy (14.7 [1.3-163]) were independently associated with a favorable prognosis. CONCLUSIONS: In defined severe neonatal enterovirus infections, serum AST level correlated with the disease severity. Early IVIG therapy, if needed, may be beneficial for survival.

A multicenter outcomes analysis of children with severe rhino/enteroviral respiratory infection.

OBJECTIVES: To investigate the impact of human rhino/enteroviruses on morbidity and mortality outcomes in children with severe viral respiratory infection. DESIGN: Retrospective cohort study. SETTING: The ICU, either PICU or cardiac ICU, at three urban academic tertiary-care children's hospitals. PATIENTS: All patients with laboratory-confirmed human rhino/enteroviruses infection between January 2010 and June 2011. INTERVENTIONS: We captured demographic and clinical data and analyzed associated morbidity and mortality outcomes. MEASUREMENTS AND MAIN RESULTS: There were 519 patients included in our analysis. The median patient age was 2.7 years. The median hospital and ICU lengths of stay were 4 days and 2 days, respectively. Thirty-four percent of patients had a history of asthma, and 25% of patients had a chronic medical condition other than asthma. Thirty-two percent of patients required mechanical ventilation. Eleven patients (2.1%) did not survive to hospital discharge. The rate of viral coinfection was 12.5% and was not associated with mortality. Predisposing factors associated with increased mortality included immunocompromised state (p < 0.001), ICU admission severity of illness score (p < 0.001), and bacterial coinfection (p = 0.003). CONCLUSIONS: There is substantial morbidity associated with severe respiratory infection due to human rhino/enteroviruses in children. Mortality was less severe than reported in other respiratory viruses such as influenza and respiratory syncytial virus. The burden of illness from human rhino/enteroviruses in the ICU in terms of resource utilization may be considerable.

Antiviral Combination Approach as a Perspective to Combat Enterovirus Infections.

Human enteroviruses distributed worldwide are causative agents of a broad spectrum of diseases with extremely high morbidity, including a series of severe illnesses of the central nervous system, heart, endocrine pancreas, skeleton muscles, etc., as well as the common cold contributing to the development of chronic respiratory diseases, including the chronic obstructive pulmonary disease. The above mentioned diseases along with the significantly high morbidity and mortality in children, as well as in the high-risk populations (immunodeficiencies, neonates) definitely formulate the chemotherapy as the main tool for the control of enterovirus infections. At present, clinically effective antivirals for use in the treatment of enteroviral infection do not exist, in spite of the large amount of work carried out in this field. The main reason for this is the development of drug resistance. We studied the process of development of resistance to the strongest inhibitors of enteroviruses, WIN compounds (VP1 protein hydrophobic pocket blockers), especially in the models in vivo, Coxsackievirus B (CV-B) infections in mice. We introduced the tracing of a panel of phenotypic markers (MIC50 value, plaque shape and size, stability at 50℃, pathogenicity in mice) for characterization of the drug-mutants (resistant and dependent) as a very important stage in the study of enterovirus inhibitors. Moreover, as a result of VP1 RNA sequence analysis performed on the model of disoxaril mutants of CVB1, we determined the molecular basis of the drug-resistance. The monotherapy courses were the only approach used till now. For the first time in the research for anti-enterovirus antivirals our team introduced the testing of combination effect of the selective inhibitors of enterovirus replication with different mode of action. This study resulted in the selection of a number of very effective in vitro double combinations with synergistic effect and a broad spectrum of sensitive enteroviruses. The most prospective attainment in our examinations in this field was the development of a novel scheme for the combined application of anti-enteroviral substances in coxsackievirus B1 neuroinfection in newborn mice. It consisted of a consecutive, alternating and non simultaneous administration of the substances in the combination. The triple combination - disoxaril- guanidine. HCl-oxoglaucine (DGO) showed a high effectiveness expressed in the marked reduction of the mortality rate in infected mice as compared both to the placebo group, and to the partner compounds used alone every day, and to the same combination applied simultaneously every day. The studies of the drug sensitivity of viral brain isolates from mice treated with DGO combination showed not only preserved, but even increased sensitivity to the drugs included in the combination. Obviously, the consecutive alternating administration of anti-enteroviral substances hinders the occurrence of drug-resistance in the course of the experimental enteroviral infections in mice.

Global reemergence of enterovirus D68 as an important pathogen for acute respiratory infections.

We previously detected enterovirus D68 (EV-D68) in children with severe acute respiratory infections in the Philippines in 2008-2009. Since then, the detection frequency of EV-D68 has increased in different parts of the world, and EV-D68 is now recognized as a reemerging pathogen. However, the epidemiological profile and clinical significance of EV-D68 is yet to be defined, and the virological characteristics of EV-D68 are not fully understood. Recent studies have revealed that EV-D68 is detected among patients with acute respiratory infections of differing severities ranging from mild upper respiratory tract infections to severe pneumonia including fatal cases in pediatric and adult patients. In some study sites, the EV-D68 detection rate was higher among patients with lower respiratory tract infections than among those with upper respiratory tract infections, suggesting that EV-D68 infections are more likely to be associated with severe respiratory illnesses. EV-D68 strains circulating in recent years have been divided into three distinct genetic lineages with different antigenicity. However, the association between genetic differences and disease severity, as well as the occurrence of large-scale outbreaks, remains elusive. Previous studies have revealed that EV-D68 is acid sensitive and has an optimal growth temperature of 33 °C. EV-D68 binds to α2,6-linked sialic acids; hence, it is assumed that it has an affinity for the upper respiratory track where these glycans are present. However, the lack of suitable animal model constrains comprehensive understanding of the pathogenesis of EV-D68.

Early dexamethasone treatment exacerbates enterovirus 71 infection in mice.

Enterovirus 71 (EV71) infection can induce encephalitis. Overt immune responses is suspected to cause severe symptoms, so anti-inflammatory agents, corticosteroids have been recommended for treatment. However, one clinical study reported that treatment with glucocorticoids, dexamethasone (Dex) exacerbates disease severity. Here we investigated Dex treatment on EV71 infection using the murine model and found that both long-term (14-day) and short-term (4-day) Dex treatment starting from 1 or 3 days postinfection increased the mortality and disease severity of infected mice. Dex treatment starting from 4 or 8 days postinfection did not affect mouse mortality and disease severity. Early Dex treatment starting from 1 day postinfection caused atrophy and enhanced apoptosis in lymphoid organs to decrease the numbers of lymphocytes (CD4(+) T cells, CD8(+) T cells, and CD19(+) B cells) and to increase viral loads in infected tissues of mice. Our results demonstrate that Dex treatment has no beneficial effect on EV71 infection.