High permissiveness for #genetic exchanges between #enteroviruses of species A, including enterovirus 71, favours #evolution through intertypic #recombination in #Madagascar (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

High permissiveness for genetic exchanges between enteroviruses of species A, including enterovirus 71, favours evolution through intertypic recombination in Madagascar

Romain Volle, Richter Razafindratsimandresy, Marie-Line Joffret, Maël Bessaud, Sendraharimanana Rabemanantsoa, Seta Andriamamonjy, Jonhson Raharinantoanina, Bruno Blondel,Jean-Michel Heraud, Jean-Luc Bailly, Francis Delpeyroux

DOI: 10.1128/JVI.01667-18



Human enteroviruses of species A (EV-A) are the leading cause of hand-foot-and-mouth disease (HFMD). EV-A71 is frequently implicated in HFMD outbreaks and can also cause severe neurological manifestations. We investigated the molecular epidemiological processes at work and the contribution of genetic recombination to the evolutionary history of EV-A in Madagascar, focusing on the recently described EV-A71 genogroup F in particular. Twenty-three EV-A isolates, mostly collected in 2011 from healthy children living in various districts of Madagascar, were characterised by whole-genome sequencing. Eight different types were identified, highlighting the local circulation and diversity of EV-A. Comparative genome analysis revealed evidence of frequent recent intra- and intertypic genetic exchanges between the non-capsid sequences of Madagascan EV-A isolates. The three EV-A71 isolates had different evolutionary histories in terms of recombination, with one isolate displaying a mosaic genome resulting from recent genetic exchanges with Madagascan coxsackieviruses A7 and possibly -A5 and -A10 or common ancestors. The engineering and characterisation of recombinants generated from progenitors belonging to different EV-A types or EV-A71 genogroups with distantly related non-structural sequences indicated a high level of permissiveness for intertypic genetic exchange in EV-A. This permissiveness suggests that the primary viral functions associated with the non-structural sequences have been highly conserved, through the diversification and evolution of the EV-A species. No outbreak of disease due to EV-A has yet been reported in Madagascar, but the diversity, circulation and evolution of these viruses justify surveillance of EV-A circulation and HFMD cases, to prevent possible outbreaks due to emerging strains.



Human enteroviruses of species A (EV-A), including EV-A71, are the leading cause of hand-foot-and-mouth disease (HFMD), and may also cause severe neurological manifestations. We investigated the circulation and molecular evolution of EV-A in Madagascar, focusing particularly on the recently described EV-A71 genogroup F. Eight different types, mostly collected in 2011, were identified, highlighting the local circulation and diversity of EV-A. Comparative genome analysis revealed evidence of frequent genetic exchanges between the different types of isolates. The three EV-A71 isolates had different evolutionary histories in terms of recombination. The engineering and characterisation of recombinants involving progenitors belonging to different EV-A types indicated a high degree of permissiveness for genetic exchange in EV-A. No outbreak of disease due to EV-A has yet been reported in Madagascar, but the diversity, circulation and evolution of these viruses justify the surveillance of EV-A circulation, to prevent possible HFMD outbreaks due to emerging strains.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Enterovirus; Recombination; EV-A71; Coxsackievirus A5-A7-A10; HFMD; Madagascar.



#Enterovirus A71 #Infection and #Neurologic Disease, Madrid, #Spain, 2016 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 1—January 2019 / CME ACTIVITY – Synopsis

Enterovirus A71 Infection and Neurologic Disease, Madrid, Spain, 2016

Carmen Niño Taravilla1  , Isabel Pérez-Sebastián1, Alberto García Salido, Claudia Varela Serrano, Verónica Cantarín Extremera, Anna Duat Rodríguez, Laura López Marín, Mercedes Alonso Sanz, Olga María Suárez Traba, and Ana Serrano González

Author affiliations: Hospital Infantil Universitario Niño Jesús, Madrid, Spain



We conducted an observational study from January 2016 through January 2017 of patients admitted to a reference pediatric hospital in Madrid, Spain, for neurologic symptoms and enterovirus infection. Among the 30 patients, the most common signs and symptoms were fever, lethargy, myoclonic jerks, and ataxia. Real-time PCR detected enterovirus in the cerebrospinal fluid of 8 patients, nasopharyngeal aspirate in 17, and anal swab samples of 5. The enterovirus was genotyped for 25 of 30 patients; enterovirus A71 was the most common serotype (21/25) and the only serotype detected in patients with brainstem encephalitis or encephalomyelitis. Treatment was intravenous immunoglobulins for 21 patients and corticosteroids for 17. Admission to the pediatric intensive care unit was required for 14 patients. All patients survived. At admission, among patients with the most severe disease, leukocytes were elevated. For children with brainstem encephalitis or encephalomyelitis, clinicians should look for enterovirus and not limit testing to cerebrospinal fluid.

Keywords: EV-A71; Encephalitis; Spain.


#Surveillance of #enteroviruses from #paediatric patients attended at a tertiary #hospital in #Catalonia from 2014 to 2017 (J Clin Virol., abstract)

[Source: Science Direct, full page: (LINK). Abstract, edited.]

Journal of Clinical Virology / Available online 30 November 2018 / In Press, Accepted Manuscript

Surveillance of enteroviruses from paediatric patients attended at a tertiary hospital in Catalonia from 2014 to 2017

Cristina Andrés a, Jorgina Vila b, Laura Gimferrer a , Maria Piñana a, Juliana Esperalba a, Maria Gema Codina a, Meritxell Barnés b, Mariadel Carmen Martín a, Francisco Fuentes a, Susana Rubio a, Pilar Alcubilla a, Carlos Rodrigo b, Tomàs Pumarola a, Andrés Antón a

{a} Respiratory Viruses Unit, Virology Section, Microbiology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; {b} Paediatric Hospitalisation Unit, Department of Paediatrics, Hospital Universitari Maternoinfantil Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Received 4 September 2018, Revised 26 October 2018, Accepted 16 November 2018, Available online 30 November 2018.

DOI: https://doi.org/10.1016/j.jcv.2018.11.004



  • The study reports virological and clinical enterovirus surveillance in Catalonia.
  • The four enterovirus species cocirculated, distinguishing up to 27 different types.
  • Most of neurological studied cases were from the 2016 spring outbreak.
  • EV-A71 was one of the most detected EV, mostly during the outbreak.
  • Rhombencephalitis cases were related to EV-A71 infection.
  • EV-D68 was associated with lower respiratory tract infections.
  • Necessity to perform EV surveillance in primary care settings.




Enterovirus (EV) infections are usually asymptomatic or mild, but symptomatic infections can evolve to severe complications. Outbreaks of EV-A71 and EV-D68 have been recently reported worldwide, sometimes related to severe clinical outcomes.


To describe EV genetic diversity and the clinical outcomes from paediatric patients attended at a tertiary university hospital in Barcelona (Catalonia, Spain) from 2014 to 2017.

Study design

Specimens were collected from paediatric (<17 years old) cases with suspicion of respiratory tract infection or EV infection. EV laboratory-confirmation was performed by specific real-time multiplex RT-PCR assay. Partial viral VP1 protein was sequenced for genetic characterisation by phylogenetic analyses.


A total of 376 (7%) from 5,703 cases were EV laboratory-confirmed. Phylogenetic analyses of VP1 (210; 81%) sequences distinguished up to 27 different EV types distributed within EV-A (82; 40%), EV-B (90; 42%), EV-C (5; 2%), and EV-D (33; 15%), in addition to 50 (19%) rhinoviruses. The most predominant were EV-A71 (37; 45%) and EV-D68 (32; 99%). EV-A71 was highly related to neurological complications (25/39, 63%), of which 20/39 were rhombencephalitis, and most EV-D68 (28/32, 88%) were associated with lower respiratory tract infections (LRTI), and exceptionally one (3%) with flaccid paralysis.


EV-A71 and EV-D68 were the most detected EV in respiratory specimens. EV-A71 was highly related to neurological disease and EV-D68 was often associated with LRTI. However, both potential relatedness to neurological diseases makes the monitoring of EV circulation obligatory.

Keywords: enteroviruses – respiratory infections – surveillance – genetic diversity – molecular epidemiology – paediatric population

© 2018 Elsevier B.V. All rights reserved.

Keywords: Enterovirus; EV-A71; EV-D68; Rhomboencephalitis; AFP; Spain.


IL-10-592 #Polymorphism is Associated with IL-10 Expression and #Severity of #Enterovirus 71 #Infection in #Chinese #Children (J Clin Virol., abstract)

[Source: Journal of Clinical Virology, full page: (LINK). Abstract, edited.]

IL-10-592 Polymorphism is Associated with IL-10 Expression and Severity of Enterovirus 71 Infection in Chinese Children

Na Zhao, Hui-lan Chen, Zhen-zhen Chen, Jing Li, Zong-bo Chen

DOI: http://dx.doi.org/10.1016/j.jcv.2017.08.005

Publication History: Published online: August 18, 2017 – Accepted: August 10, 2017 – Received in revised form: July 18, 2017 – Received: April 11, 2017



  • IL-10-592 C allele is related to critical EV71 infection.
  • IL-10-592 A/A could decrease IL-10 level.
  • IL-10 in plasma was elevated in critical EV71 infection cases.




Enterovirus 71 (EV71) infection results in some severe complications with high mortality and disability in Hand, Foot and Mouth Disease (HFMD) in children. Recent studies have shown that cytokine genetic predispositions have associations with both the development of EV71 infection and severity of HFMD.


This study was designed to investigate whether the IL-10–592 polymorphism is associated with IL-10 levels and disease severity in Chinese children with EV71 infection.

Study design

In patients selected, there were 378 cases with EV71 infection (including 291 mild cases, 70 severe cases and 17 critical cases), as well as 406 health controls. EV71 in serum was tested by RT-PCR, and IL-10-592 genotype was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis techniques.


The IL-10-592C allele was observed with higher frequency in patients with critical EV71 infection (70.59%) compared with severe EV71 infection (41.43%, P < 0.01), mild EV71 infection (43.81%, P < 0.01) and healthy children (44.46%, P < 0.01). The blood IL-10 levels of critical cases were significantly higher than severe cases, mild cases, and healthy children. Among all of the four groups, IL-10 levels in patients with genotype AA were significantly lower than those with genotypes AC + CC (t = 4.86, P < 0.05; t = 2.30, P < 0.05; t = 3.44, P < 0.05; t = 5.58, P < 0.05).


IL-10-592C allele is associated with IL-10 expressions and the severity of EV71 infection in Chinese patients.

Keywords: Enterovirus 71 infection, IL-10, Gene polymorphism

Keywords: EV-71; Enterovirus; HFMD; China; Genetics.


An inactivated #HFMD #vaccine using the #EV71 (C4a) strain isolated from a #Korean patient induces a strong immunogenic response in mice (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]


An inactivated hand-foot-and-mouth disease vaccine using the enterovirus 71 (C4a) strain isolated from a Korean patient induces a strong immunogenic response in mice

Hyun Ju In , Heeji Lim , Jung-Ah Lee, Hye Jin Kim, Jin-Won Kim, Ji-Yeon Hyeon, Sang-Gu Yeo, June-Woo Lee, Jung Sik Yoo, Young Ki Choi, Sang-Won Lee

Published: May 24, 2017 / https://doi.org/10.1371/journal.pone.0178259



Enterovirus 71 (EV71) is a major causative agent of hand-foot-and-mouth disease (HFMD) frequently occurring in children. HFMD induced by EV71 can cause serious health problems and has been reported worldwide, particularly in the Asia-Pacific region. In this study, we assessed the immunogenicity of a formalin-inactivated HFMD vaccine using an EV71 strain (FI-EV71 C4a) isolated from a Korean patient. The vaccine candidate was evaluated in mice to determine the vaccination doses and vaccine schedules. BALB/c mice were intramuscularly administered 5, 10, or 20 μg FI-EV71 vaccine, followed by a booster 2 weeks later. EV71-specific antibodies and neutralizing antibodies were induced and maintained until the end of the experimental period in all vaccinated groups. To determine the effectiveness of adjuvant for the EV71 vaccine, three adjuvants, i.e., aluminium hydroxide gel, monophosphoryl lipid A, and polyinosinic-polycytidylic acid, were administered separately with the FI-EV71 vaccine to mice via the intramuscular route. Mice administered the FI-EV71 vaccine formulated with all three adjuvants induced a significantly increased antibody response compared with that of the single adjuvant groups. The vaccinated group with triple adjuvants exhibited more rapid induction of EV71-specific and neutralizing antibodies than the other groups. These results suggested that the role of adjuvant in inactivated vaccine was important for eliciting effective immune responses against EV71. In conclusion, our results showed that FI-EV71 was a potential candidate vaccine for prevention of EV71 infection.


Citation: In HJ, Lim H, Lee J-A, Kim HJ, Kim J-W, Hyeon J-Y, et al. (2017) An inactivated hand-foot-and-mouth disease vaccine using the enterovirus 71 (C4a) strain isolated from a Korean patient induces a strong immunogenic response in mice. PLoS ONE 12(5): e0178259. https://doi.org/10.1371/journal.pone.0178259

Editor: Ralph Tripp, University of Georgia, UNITED STATES

Received: February 7, 2017; Accepted: April 26, 2017; Published: May 24, 2017

Copyright: © 2017 In et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are included within the paper and its Supporting Information files.

Funding: This work was supported by grants from the Korea National Institute of Health (grant no. NIH 4800-4845-300). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Enterovirus 71; HFMD; Vaccines.


#Clinical #Characteristics and Functional #Motor #Outcomes of #Enterovirus 71 #Neurological #Disease in #Children (JAMA Neurol., #abstract)

[Source: The Journal of the American Medical Association (JAMA) Neurology, full page: (LINK). Abstract, edited.]

Original Investigation | March 2016

Clinical Characteristics and Functional Motor Outcomes of Enterovirus 71 Neurological Disease in Children [      ]

Hooi-Ling Teoh, MBBS1,2; Shekeeb S. Mohammad, FRACP3,4; Philip N. Britton, FRACP4,5,6; Tejaswi Kandula, FRACP1; Michelle S. Lorentzos, MBBS3; Robert Booy, PhD4,5,7; Cheryl A. Jones, PhD4,5,6; William Rawlinson, PhD8; Vidiya Ramachandran, MBBS8; Michael L. Rodriguez, FRCPA9; P. Ian Andrews, FRACP1; Russell C. Dale, PhD3,4; Michelle A. Farrar, PhD1,2; Hugo Sampaio, FRACP1,2

Author Affiliations: 1Department of Neurology, Sydney Children’s Hospital, Sydney, Australia 2Discipline of Pediatrics, School of Women’s and Children’s Health, UNSW Medicine, The University of New South Wales, Sydney, Australia 3T. Y. Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, Australia 4Discipline of Pediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, Australia 5Marie Bashir Institute, Sydney Medical School, University of Sydney, Sydney, Australia 6Department of Infectious Diseases and Microbiology, The Children’s Hospital at Westmead, Sydney, Australia
7National Centre for Immunization Research and Surveillance, Kid’s Research Institute, Sydney, Australia 8Serology and Virology Division, Prince of Wales Hospital, Sydney, Australia 9Department of Forensic Medicine, NSW Health Pathology, Sydney, Australia

JAMA Neurol. 2016;73(3):300-307. doi:10.1001/jamaneurol.2015.4388.




Enterovirus 71 (EV71) causes a spectrum of neurological complications with significant morbidity and mortality. Further understanding of the characteristics of EV71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines.


To further characterize EV71-related neurological disease and neurological outcome in children.

Design, Setting, and Participants

Prospective 2-hospital (The Sydney Children’s Hospitals Network) inpatient study of 61 children with enterovirus-related neurological disease during a 2013 outbreak of EV71 in Sydney, Australia. The dates of our analysis were January 1, to June 30, 2013.

Main Outcomes and Measures

Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed.


Among 61 patients, there were 4 precipitous deaths (7%), despite resuscitation at presentation. Among 57 surviving patients, the age range was 0.3 to 5.2 years (median age, 1.5 years), and 36 (63%) were male. Fever (100% [57 of 57]), myoclonic jerks (86% [49 of 57]), ataxia (54% [29 of 54]), and vomiting (54% [29 of 54]) were common initial clinical manifestations. In 57 surviving patients, EV71 neurological disease included encephalomyelitis in 23 (40%), brainstem encephalitis in 20 (35%), encephalitis in 6 (11%), acute flaccid paralysis in 4 (7%), and autonomic dysregulation with pulmonary edema in 4 (7%). Enterovirus RNA was more commonly identified in feces (42 of 44 [95%]), rectal swabs (35 of 37 [95%]), and throat swabs (33 of 39 [85%]) rather than in cerebrospinal fluid (10 of 41 [24%]). Magnetic resonance imaging revealed characteristic increased T2-weighted signal in the dorsal pons and spinal cord. All 4 patients with pulmonary edema (severe disease) demonstrated dorsal brainstem restricted diffusion (odds ratio, 2; 95% CI, 1-4; P = .001). Brainstem or motor dysfunction had resolved in 44 of 57 (77%) at 2 months and in 51 of 57 (90%) at 12 months. Focal paresis was evident in 23 of 57 (40%) at presentation and was the most common persisting clinical and functional problem at 12 months (observed in 5 of 6 patients), with 1 patient also requiring invasive ventilation. Patients initially seen with acute flaccid paralysis or pulmonary edema had significantly greater frequencies of motor dysfunction at follow-up compared with patients initially seen with other syndromes (odds ratio, 15; 95% CI, 3-79; P < .001).

Conclusions and Relevance

Enterovirus 71 may cause serious neurological disease in young patients. The distinct clinicoradiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of gray matter in the brainstem or spinal cord.

Keywords: Research; Abstracts; Enterovirus 71; Encephalitis.