Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016

Abstract

Enterovirus 71 (EV-A71) is a small, non-enveloped, single-stranded RNA virus that belongs to the species Enterovirus A along with 24 other serotypes within the Enterovirus genus [1]. According to the VP1 protein sequence, EV-A71 is classified into six genogroups (A–F) and a number of subgenogroups (B0–B5, C1–C5) [2]. Although EV-A71 infection is often asymptomatic, it can cause disorders with a wide range of clinical manifestations from non-specific febrile illness, aseptic meningitis and mild mucocutaneous symptoms to severe neurological diseases such as brainstem encephalitis and acute flaccid paralysis (AFP) [3,4]. EV-A71 is distributed worldwide. However, the largest outbreaks associated with hand, foot and mouth disease (HFMD) with subsequent neurological and cardiopulmonary complications have been described in the Asia-Pacific region, especially in the past 20 years [2,5-7]. These outbreaks have been connected to the circulation of different subgenogroups (B3, B4, C1, C2 and C4) [8-14]. In Europe, although outbreaks of polio-like disease occurred in Hungary and Bulgaria in the 1970s [15,16], only sporadic cases have been reported from several countries in recent years, mainly caused by the C1 and C2 subgenogroups [2,17]. In 2015, a new recombinant EV-A71 variant was identified that affected at least 19 young children in different areas of Germany [18]. This infection was associated with neurological manifestations (cerebral seizures, myoclonia and ataxia) that required hospitalisation. There were no reports of fatal cases or clinical sequelae after hospital discharge. Moreover, a well-documented case, a 2-year-old girl, required hospitalisation and was diagnosed with brainstem encephalitis and cardiopulmonary complications with an outcome of a probable persistent neurological impairment [19]. In addition, 18 cases of severe neurological disease associated with EV-A71 infection, and phylogenetically closely related to the strains described in Germany, were reported in France between May and October 2016. Patients presented with rhombencephalitis, encephalitis or encephalomyelitis, and one fatal case of acute cardiac failure was reported [20]. The same strain was also involved in a sporadic case of encephalitis in Poland during summer 2016 [21]. In Spain, EV-A71 was circulating at a very low rate until 2015 [22,23]. In the spring of 2016, however, a large outbreak associated with severe neurological diseases was reported in the region of Catalonia [24-26] and further disseminated to the rest of the country. In the present study, we investigated the clinical manifestations of EV-A71 infections and the molecular epidemiology and geographical spread of the strains detected in Spain in 2016, comparing them to strains circulating in Spain and other countries in recent years.