Outbreak of Enterovirus Infection with Neurological Presentations in a Pediatric Population in Northern Spain: A Clinical Observational Study

Abstract

Objective The study aimed to describe the cases of neurological disease related to the outbreak of enterovirus (EV) in three regions in Northern Spain during 2016.

Materials and Methods Multicenter retrospective observational study. Clinical, radiological, and microbiological data were analyzed from patients younger than 15 years with confirmed EV-associated neurological disease admitted to 10 hospitals of Asturias, Cantabria, and Castile and Leon between January 1 and December 31, 2016.

Results Fifty-five patients were included. Median age was 24 months (interquartile range = 18.5 months). Fifteen patients were classified as aseptic meningitis (27.3%). In total, 37 cases presented brainstem encephalitis (67.3%), 25 of them due to EV-A71 with excellent prognosis (84.6% asymptomatic 2 months following the onset). Three cases of acute flaccid myelitis (5.5%) by EV-D68 were reported and presented persistent paresis 2 months following the onset. Microbiological diagnosis by reverse transcriptase polymerase chain reaction was performed in all cases, finding EV in cerebrospinal fluid in meningitis, but not in brainstem encephalitis and acute flaccid myelitis, where EV was found in respiratory or rectal samples. Step therapy was administrated with intravenous immunoglobulin (IVIG; 32.7%), methylprednisolone (10%), and plasmapheresis (3.6%). Four patients received fluoxetine (7.3%). Twenty patients needed to be admitted to pediatric intensive care unit (36.4%).

Conclusion Clinical, microbiological, and radiological diagnosis is essential in outbreaks of EV neurological disease, taking into account that it can be difficult to identify EV-A71 and EV-D68 in CSF, requiring throat or rectal samples. There is not specific treatment to these conditions and the efficacy and understanding of the mechanism of action of immune-modulatory treatment (IVIG, corticosteroids, and plasmapheresis) is limited.

Keywords

enterovirus - rhombencephalitis - brainstem encephalitis - acute flaccid myelitis - enterovirus A-71 - enterovirus D-68

Publikationsverlauf

Eingereicht: 15. Oktober 2020

Angenommen: 14. Januar 2021

Artikel online veröffentlicht:
03. März 2021

• References

• 1 Chen B-S, Lee H-C, Lee K-M, Gong Y-N, Shih S-R. Enterovirus and Encephalitis. Front Microbiol 2020; 11 (February): 261
• 2 Sawyer MH. Enterovirus infections: diagnosis and treatment. Semin Pediatr Infect Dis 2002; 13 (01) 40-47
• 3 Gray JA, Moffat MAJ, Sangster G. Viral meningitis. A 10-year study. Scott Med J 1969; 14 (07) 234-242
• 4 Rudolph H, Schroten H, Tenenbaum T. Enterovirus infections of the central nervous system in children: an update. Pediatr Infect Dis J 2016; 35 (05) 567-569
• 5 Ho M, Chen E-R, Hsu K-H. et al; Taiwan Enterovirus Epidemic Working Group. An epidemic of enterovirus 71 infection in Taiwan. N Engl J Med 1999; 341 (13) 929-935
• 6 Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. N Engl J Med 1999; 341 (13) 936-942
• 7 González-Sanz R, Casas-Alba D, Launes C. et al. Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016. Euro Surveill 2019;24(07):
• 8 Casas-Alba D, de Sevilla MF, Valero-Rello A. et al. Outbreak of brainstem encephalitis associated with enterovirus-A71 in Catalonia, Spain (2016): a clinical observational study in a children's reference centre in Catalonia. Clin Microbiol Infect 2017; 23 (11) 874-881
• 9 Andrés C, Vila J, Gimferrer L. et al. Surveillance of enteroviruses from pediatric patients attended at a tertiary hospital in Catalonia from 2014 to 2017. J Clin Virol 2019; 110: 29-35
• 10 Leal Barceló AM, Carrascosa García P, Rincón López EM, Miranda Herrero MC, Navarro ML. Brote de infección por enterovirus causantes de afectación neurológica grave en un hospital terciario. An Pediatr (Barc) 2018; 89 (06) 378-381
• 11 Taravilla CN, Pérez-Sebastián I, Salido AG. et al. Enterovirus A71 infection and neurologic disease, Madrid, Spain, 2016. Emerg Infect Dis 2019; 25 (01) 25-32
• 12 Reina J, Cabrerizo M, Ferrés F. Análisis de las características clínicas de las infecciones causadas por el enterovirus A71 (EV-A71) en las Islas Baleares. An Pediatr (Barc) 2017; 87 (05) 289-290
• 13 Valdivielso Martínez AI, Carazo Gallego B, Cubiles Arilo Z, Moreno-Pérez D, Urda Cardona A. Patología neurológica aguda por enterovirus: revisión de casos clínicos en un hospital andaluz de tercer nivel tras brote epidémico de Cataluña. An Pediatr (Barc) 2018; 89 (04) 249-251
• 14 Cabrerizo M, Díaz-Cerio M, Muñoz-Almagro C. et al. Molecular epidemiology of enterovirus and parechovirus infections according to patient age over a 4-year period in Spain. J Med Virol 2017; 89 (03) 435-442
• 15 Karrasch M, Fischer E, Scholten M. et al. A severe pediatric infection with a novel enterovirus A71 strain, Thuringia, Germany. J Clin Virol 2016; 84: 90-95
• 16 Böttcher S, Obermeier PE, Neubauer K, Diedrich S. Laboratory Network for Enterovirus Diagnostics. Recombinant enterovirus A71 subgenogroup C1 strains, Germany, 2015. Emerg Infect Dis 2016; 22 (10) 1843-1846
• 17 Antona D, Kossorotoff M, Schuffenecker I. et al. Severe paediatric conditions linked with EV-A71 and EV-D68, France, May to October 2016. Euro Surveill 2016;21(46):
• 18 Cabrerizo M, García-Iñiguez JP, Munell F. et al. First cases of severe flaccid paralysis associated with enterovirus d68 infection in Spain, 2015-2016. Pediatr Infect Dis J 2017; 36 (12) 1214-1216
• 19 González-Sanz R, Taravillo I, Reina J. et al. Enterovirus D68-associated respiratory and neurological illness in Spain, 2014-2018. Emerg Microbes Infect 2019; 8 (01) 1438-1444
• 20 Instituto Nacional de Estadística (Spanish Statistics National Institute). Population by communities, age, sex and year. Spain; 2016. . Accessed April 20, 2020 at: www.ine.es
• 21 World Health Organisation. A Guide to Clinical Management and Public Health Response for Hand, Foot, and Mouth Disease. 2010
• 22 Leshem E. Acute flaccid myelitis among persons aged ≤21 years United States, August 1–november 13, 2014. Morb Mortal Wkly Rep 2015; 63 (53) 1243-1244
• 23 Khanh TH, Sabanathan S, Thanh TT. et al. Enterovirus 71-associated hand, foot, and mouth disease, Southern Vietnam, 2011. Emerg Infect Dis 2012; 18 (12) 2002-2005
• 24 Saunders NR, Dreifuss J-J, Dziegielewska KM. et al. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front Neurosci 2014; 8: 404
• 25 Lee T-C, Guo H-R, Su H-JJ, Yang Y-C, Chang H-L, Chen K-T. Diseases caused by enterovirus 71 infection. Pediatr Infect Dis J 2009; 28 (10) 904-910
• 26 Sejvar JJ, Lopez AS, Cortese MM. et al. Acute flaccid myelitis in the United States, August-December 2014: results of nationwide surveillance. Clin Infect Dis 2016; 63 (06) 737-745
• 27 Messacar K, Asturias EJ, Hixon AM. et al. Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality. Lancet Infect Dis 2018; 18 (08) e239-e247
• 28 Wang SM, Lei HY, Liu CC. Cytokine immunopathogenesis of enterovirus 71 brain stem encephalitis. Clin Dev Immunol 2012; 2012: 876241
• 29 Wang SM, Lei HY, Huang MC. et al. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol 2006; 37 (01) 47-52
• 30 Chea S, Cheng YB, Chokephaibulkit K. et al. Workshop on use of intravenous immunoglobulin in hand, foot and mouth disease in Southeast Asia. Emerg Infect Dis 2015;
• 31 Ulferts R, van der Linden L, Thibaut HJ. et al. Selective serotonin reuptake inhibitor fluoxetine inhibits replication of human enteroviruses B and D by targeting viral protein 2C. Antimicrob Agents Chemother 2013; 57 (04) 1952-1956
• 32 Rhoden E, Zhang M, Nix WA, Oberste MS. In vitro efficacy of antiviral compounds against enterovirus D68. Antimicrob Agents Chemother 2015; 59 (12) 7779-7781
• 33 Tyler KL. Rationale for the evaluation of fluoxetine in the treatment of enterovirus D68-associated acute flaccid myelitis. JAMA Neurol 2015; 72 (05) 493-494
• 34 Messacar K, Sillau S, Hopkins SE. et al. Safety, tolerability, and efficacy of fluoxetine as an antiviral for acute flaccid myelitis. Neurology 2019; 92 (18) e2118-e2126