An In Vivo Model of Echovirus-Induced Meningitis Defines the Differential Roles of Type I and Type III Interferon Signaling in Central Nervous System Infection.

Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation are poorly understood, owing at least in part to the lack of in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an in vivo neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We show that expression of the human homologue of the primary echovirus receptor, the neonatal Fc receptor (FcRn), is not sufficient for infection of the brains of neonatal mice. However, ablation of type I, but not III, interferon (IFN) signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms, including delayed motor skills and hind-limb weakness. Using this model, we defined the immunological response of the brain to echovirus infection and identified key cytokines, such as granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6), that were induced by this infection. Lastly, we showed that echoviruses specifically replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an in vivo model of aseptic meningitis associated with echovirus infections that delineates the differential roles of type I and type III IFNs in echovirus-associated neuronal disease and defines the specificity of echoviral infections within the meninges. IMPORTANCE Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the FcRn, the primary receptor for echoviruses, and ablation of type I IFN signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.

Clinical characteristics of echovirus 11 and coxsackievirus B5 infections in Taiwanese children requiring hospitalization.

BACKGROUND: Severe illness can occur in young children infected with certain types of enteroviruses including echovirus 11 (Echo11) and coxsackievirus B5 (CoxB5). The manifestations and outcomes of Echo11 and CoxB5 diseases across all ages of children remained not comprehensively characterized in Taiwan. METHODS: Culture-confirmed Echo11 (60 patients) or CoxB5 (65 patients) infections were identified in a hospital from 2010 to 2018. The demographics, clinical presentations, laboratory data and outcomes were abstracted and compared between the two viruses infections. RESULTS: Echo11 and CoxB5 was respectively identified in 7 (77.8%) and 2 (22.2%) of 9 calendar years. The median age of all patients was 15 months (range, 1 day-14.5 years). For infants ≤3 months old, Echo11 (23 cases) was associated with higher incidence of aseptic meningitis (35% versus 0%, P = 0.003), and a lower rate of upper respiratory tract infections (URI) (22% versus 65%, P = 0.004) compared to CoxB5 (20 cases) infections. For patients >3 months old, URI was the cardinal diagnosis (60%) for both viruses. Aseptic meningitis was also more commonly identified in elder children with Echo11 infections (27% versus 11%), though with marginal significance (P = 0.07). Acute liver failure was identified in four young infants with Echo11 infections including one neonate dying of severe sepsis and myocarditis. All patients with CoxB5 infections recovered uneventfully. CONCLUSION: Aseptic meningitis, sepsis-like illness and acute liver failure were more commonly identified in children with Echo11 than those with CoxB5 infections, suggesting greater neurological tropism and virulence toward Echo11.

Viral exanthems: An update on laboratory testing of the adult patient.

Although classic viral exanthems of childhood are well described, they are rarely differentiated in adults. Laboratory techniques for viral identification have advanced without substantial literature to suggest how a dermatologist ought to conduct a cost-effective and diagnostic viral panel. Certain clinical features such as petechiae, vesicles, and dusky macular or morbilliform exanthems point strongly toward a viral exanthem. Differentiation of drug and viral causes of morbilliform eruptions has proven difficult. It is possible that with further diagnostic refinement that unnecessary and fruitless workups of an exanthem and unneeded discontinuation of drugs can be avoided. We review viral exanthems based on clinical features and discuss the available and optimal laboratory techniques to assist the dermatologist in a targeted workup.

Lower anti-echovirus antibody responses in children presenting to hospital with asthma exacerbations.

BACKGROUND: Rhinoviruses from the Enterovirus genus cause frequent infections and induce remarkably high titres of anticapsid antigen antibodies in asthmatics, while the prevalence of neutralising antibodies to the gut-trophic echoviruses from the same genus is diminished. OBJECTIVE: To assess the absolute and specific antibody titres to VP1 antigens of the gut-trophic enteroviruses, echovirus 30 and Sabin 1 poliovirus, in asthmatic and non-asthmatic children. METHODS: Recombinant polypeptides representing the VP1 capsid antigens of echovirus 30 and Sabin poliovirus 1 were produced. Their ability to bind IgG1 antibodies from the plasma of asthmatic (n = 45) and non-asthmatic (n = 29) children were quantitated by immunoassays that incorporated immunoabsorptions to remove cross-reactivity. RESULTS: The IgG1 antibody titres and prevalence of antibody binding to echovirus 30 were significantly lower for asthmatic children compared to controls (P < 0.05) and inversely correlated with total IgE levels for the whole study population (r = -0.262; P < 0.05). There was no difference in the prevalence and titre between groups to the VP1 antigen of Sabin poliovirus. Anti-tetanus toxoid titres measured for comparison did not correlate with anti-echovirus or poliovirus, but correlated with anti-rhinovirus titres in controls but not asthmatics, where the titres were higher for the asthmatic group. CONCLUSIONS AND CLINICAL RELEVANCE: The associations of lower antibody titres of asthmatic children to echovirus reported here and those of our previous findings of a heightened response to rhinovirus suggest a dichotomy where respiratory enterovirus infection/immunity increases the probability of developing asthma and enteric infections lower the risk. This provides further support for the concept of intestinal infection playing a key role in the development of allergic respiratory disease.

A case of congenital Echovirus 11 infection acquired early in pregnancy.

Enterovirus (EV) maternal infection during pregnancy and its relation to fetal developmental pathology are seldomly described. When reported, the main manifestations of EV congenital infections are myocarditis or intra-uterine fetal demise (IUFD). No information on intrauterine Echovirus 11 infection or the effect of transplacental Echovirus 11 infection on development of the fetus has been described in literature up to date (excluding late-pregnancy infections). We report here a case of an extreme form of pulmonary hypoplasia in a neonate, characterized by total failure of development of terminal respiratory units. This pregnancy was marked by spontaneous demise of a co-twin at 14 weeks of gestation (WG), as well as by positive PCR for EV (Echovirus 11 serotype) in the amniotic fluid, performed for moderate pericardial effusion at 22WG. No signs of cardiac disease were further observed, but at 32WG a bilateral abnormal lung development was noticed After spontaneous delivery at 38WG, the child could not be resuscitated, and died at one hour after birth. Pulmonary hypoplasia is usually described following decrease intrapulmonary pressure due to oligohydramnios or compression due to intrathoracic mass of variable cause. However, rare cases of primary pulmonary hypoplasia are also described and usually of unknown etiology. The coexistence in our case of a congenital EV infection and a severe primary pulmonary hypoplasia with congenital acinar aplasia, challenges our understanding of the pathogenesis of this severe pulmonary growth arrest.

Severe hepatitis associated with an echovirus 18 infection in an immune-compromised adult.

Enteroviruses are recognized as important pathogens in pediatric patients; however, they are often overlooked as etiologic agents of disease in adults. Here, we report a case of echovirus 18-associated severe systemic infection and acute liver failure in an adult hematopoietic stem cell transplant recipient. Additionally, we illustrate the utility of molecular methods for the detection and typing of enteroviral infections.

Echovirus 19 associated with a case of acute flaccid paralysis.

Acute flaccid paralysis can be caused by many members of the enterovirus genus, most notably the three poliviruses types 1 to 3. We report the case of acute flaccid paralysis caused by echovirus 19. The Western Pacific region has been declared polio free by the WHO since 2000. Australia is now using inactivated polio vaccine in the National Immunization Schedule. This vaccine does not carry the extremely rare risk of vaccine associated acute flaccid paralysis but it does leave our newly vaccinated population open gastrointestinal infection with polioviruses and the risk of circulation of the wild-type virus. Continued surveillance of cases of acute flaccid paralysis is to detect polioviruses is essential until poliovirus is completely eradicated.

Enteroviral meningitis and concurrent peripheral motor axonal polyneuropathy.

Enteroviral infections can cause acute flaccid paralysis resulting from anterior myelitis, but the occurrence of axonal polyneuropathy is not well described. We report an 8-year-old boy who presented with symmetric, ascending flaccid paralysis and was diagnosed with concurrent echovirus type 9 viral meningitis.

[Cardiac arrest: fatal presentation of viral myocarditis]. / Parada cardíaca: presentación mortal de una miocarditis viral.

Myocarditis is an inflammatory disease of the myocardium accompanied by necrosis of myocytes. The main causes are viral infections. The clinical presentation varies from mild forms to devastating ones which usually begin with trivial symptoms with progression, in some cases, to death. We report the case of an 18 month-old male toddler consulting for asthenia and anorexia for the last 24h and a previous history of respiratory tract infection with high fever in the last week. Upon arrival at the emergency room and during the first hours of admission, physical examination was perfectly normal. Later, his general state gradually deteriorated,with biochemical disturbances (metabolic acidosis, renal failure and hyperglycaemia) and, eventually, a sudden cardiac arrest, with no response to cardiopulmonary resuscitation manoeuvres.

Genetic and phenotypic diversity of echovirus 30 strains and pathogenesis of type 1 diabetes.

Several enterovirus serotypes should be considered as potentially diabetogenic. The capacity of an enterovirus to kill or impair the functions of human beta-cells can vary among the strains within a given serotype as shown previously for echovirus 9 and 30 (E-30). The evolution of E-30 has also shown patterns correlating with the global increase of type 1 diabetes incidence. In the present study, antigenic properties of a set of E-30 isolates were investigated and the results correlated with the previously documented beta-cell destructive phenotype of the strains, or to genetic clustering of the strains. No simple correlation between the three properties was observed. A full-length infectious clone was constructed and sequenced from one of the isolates found to be most destructive to beta-cells (E-30/14916net87). Phylogenetic analyses demonstrated that this strain was closely related to the E-30 prototype strain at the capsid coding region while outside the capsid region prototype strains of several other human enterovirus B serotypes clustered more closely. This suggests that the relatively greater pathogenicity of the strain might be based on properties of the genome outside of the structural protein coding region. Neutralizing antibody assays on sera from 100 type 1 diabetic patients and 100 controls using three different E-30 strains did not reveal differences between the groups. This finding does not support a previous proposition of aberrant antibody responses to E-30 in diabetic patients. It is concluded that identification of the genetic counterparts of pathogenicity of E-30 strains requires further studies.

[Acute myocarditis caused by ECHO virus].

Enteroviral infection is characterized by clinical polymorphism. One of its clinical manifestation is myocarditis, which is usually caused by Coxsackie virus. ECHO viruses cause the disease mostly in childhood. The article presents a case of enteroviral (ECHO) infection complicated by pneumonia and focal myocarditis in a 41-year-old patient, hospitalized during a season of influenza and acute respiratory infections. Acute myocarditis was moderate and the patient recovered by day 23.

Fatal echovirus 18 leukoencephalitis in a child.

Rare cases of leukoencephalitis have been reported in infants with documented enterovirus (EV) central nervous system (CNS) infections. A case of fatal encephalitis with white matter lesions caused by echovirus 18 is described, and it highlights the role of EV CNS infection as a potential cause of leukoencephalitis in infants.

Fatal illness associated with pulmonary hypertension in a neonate caused by intrauterine echovirus 11 infection.

Nonpolio enterovirus (NPEV) infections are known to cause a wide range of illnesses in the neonatal period. In most cases, NPEV is presumed to be contracted during birth. Intrauterine NPEV infections occur infrequently. A case of intrauterine echovirus 11 infection with pneumonia, persistent pulmonary hypertension of the newborn, and purpura fulminans is presented.

A neonatal echovirus 11 outbreak in an obstetric clinic.

An echovirus 11 outbreak occurred among neonates in an obstetric clinic in November 2003. Thirteen neonates were transferred to our medical center, and all were found to have echovirus 11 infection. Viral studies were performed for 32 other infants born in the clinic during the same period, including 30 asymptomatic neonates and 2 febrile infants transferred to another hospital. Two of the asymptomatic infants had echovirus 11 isolated from rectal swabs. The first patient transferred to our medical center developed extensive hemorrhage and died 6 days later. Three family members of this infant were also proved to have echovirus 11 infections. One other infant had a fulminant course and had residual hepatic impairment. The other infants had no complications. Viral studies in the 24 nursery staff were all negative. This outbreak shows how a neonatal enterovirus outbreak can occur in a nursery, starting from an infected infant in the incubation period. Early recognition and prompt management of an outbreak is important to prevent further spread of the infection.

[Acute enterovirus uveitis in infants].

Enterovirus uveitis (EU) is a new infant eye disease that was first detected and identified in Russia in 1980-1981. Three subtypes of human echoviruses (EV19K, EV11A, and EV11/B) caused 5 nosocomial outbreaks of EU in different Siberian cities and towns in 1980-1989, by affecting more than 750 children mainly below one year of age. Sporadic and focal EU cases (more than 200) were also retrospectively diagnosed in other regions of Russia and in different countries of the former Soviet Union. There were following clinical manifestations: common symptoms of the infection; acute uveitis (rapid focal iridic destruction, pupillary deformities, formation of membranes in the anterior chamber of the eye); and in 15-30% of cases severe complications, cataract, glaucoma, vision impairments. Uveitis strains EV19 and EV11 caused significant uveitis in primates after inoculation into the anterior chamber of the eye, as well as sepsis-like fatal disease with liver necrosis after venous infection. The uveitis strains are phylogenetically and pathogenetically close for primates to strains EV19 and EV11 isolated from young children with sepsis-like disease. The contents of this review have been published in the Reviews in Medical Virology, 2004, vol. 14, p. 241-254.

Masticator myopathy.

A 31-year-old woman developed low-grade fever and pain and swelling of the masticatory muscles. A T2-weighted magnetic resonance image showed high signal intensity in these muscles. Coxsackie B3 and echo 30 viruses were detected from a nasopharyngeal swab and feces, respectively. The clinical symptoms accompanied a marked decline in the serum immunoglobulin G level with progressive eosinophilia. Her symptoms disappeared by 8 weeks after onset. She was diagnosed as having masticator myopathy, which has rarely been reported in humans. The present case suggests that masticator myopathy is associated with coxsackie or echo virus infection.