Enterovirus D68 disease burden and epidemiology in hospital‐admitted influenza‐like illness, Valencia region of Spain, 2014–2020 influenza seasons

<jats:title>Abstract</jats:title><jats:p>Enterovirus D68 (EV‐D68) is an emerging agent for which data on the susceptible adult population is scarce. We performed a 6‐year analysis of respiratory samples from influenza‐like illness (ILI) admitted during 2014‐2020 in 4‐10 hospitals in the Valencia Region, Spain. EV‐D68 was identified in 68 (3.1%) among 2210 Enterovirus (EV)/Rhinovirus (HRV) positive samples. Phylogeny of 59 VP1 sequences showed isolates from 2014 clustering in B2 (6/12), B1 (5/12), and A2/D1 (1/12) subclades; those from 2015 (<jats:italic>n</jats:italic> = 1) and 2016 (<jats:italic>n</jats:italic> = 1) in B3 and A2/D1, respectively; and isolates from 2018 in A2/D3 (42/45), and B3 (3/45). B1 and B2 viruses were mainly detected in children (80% and 67%, respectively); B3 were equally distributed between children and adults; whereas A2/D1 and A2/D3 were observed only in adults. B3 viruses showed up to 16 amino acid changes at predicted antigenic sites. In conclusion, two EV‐D68 epidemics linked to ILI hospitalized cases occurred in the Valencia Region in 2014 and 2018, with three fatal outcomes and one ICU admission. A2/D3 strains from 2018 were associated with severe respiratory infection in adults. Because of the significant impact of non‐polio enteroviruses in ILI and the potential neurotropism, year‐round surveillance in respiratory samples should be pursued.</jats:p>