Enterovirus D68 and Human Respiratory Infections

Abstract

Enterovirus D68 (EV-D68) is a member of the species Enterovirus D in the genus Enterovirus of the Picornaviridae family. EV-D68 was first isolated in the United States in 1962 and is primarily an agent of respiratory disease. Infections with EV-D68 have been rarely reported until recently, when reports of EV-D68 associated with respiratory disease increased notably worldwide. An outbreak in 2014 in the United States, for example, involved more than 1,000 cases of severe respiratory disease that occurred across almost all states. Phylogenetic analysis of all EV-D68 sequences indicates that the circulating strains of EV-D68 can be classified into two lineages, lineage 1 and lineage 2. In contrast to the prototype Fermon strain, all circulating strains have deletions in their genomes. Respiratory illness associated with EV-D68 infection ranges from mild illness that just needs outpatient service to severe illness requiring intensive care and mechanical ventilation. To date, there are no specific medicines and vaccines to treat or prevent EV-D68 infection. This review provides a detailed overview about our current understanding of EV-D68-related virology, epidemiology and clinical syndromes, pathogenesis, and laboratory diagnostics.

Fig. 1

Schematic of the EV-D68 genome. The EV-D68 genome contains the genome-linked protein VPg at the 5′ end, a 5′ untranslated region (UTR), a single open reading frame codes a polyprotein, a 3′ UTR, and the poly (A) tail. The polyprotein is cleaved into 11 individual viral proteins by two viral proteases, 2A^pro and 3C^pro, during translation. Proteases and RNA-dependent RNA polymerase (RDRP) are indicated in the schematic.

Fig. 2

Maximum clade credibility tree based on Bayesian timescale phylogenetic analysis of EV-D68. The tree was inferred using partial VP1 sequences of EV-D68 strains worldwide available in GenBank as of March 23, 2015. These sequences are 339 nucleotides in length and correspond to nucleotide positions 2,521 to 2,859 of the EV-D68 prototype strain Fermon [AY426531]. The two lineages are marked by vertical lines. The strains that have complete genome sequences are indicated by black circles.

Fig. 3

Nucletide alignment of all available complete EV-D68 genomes in GenBank. Nucletides are numbered relative to the start of the Fermon strain (AY426531) of EV-D68. The strains are indicated by Genbank accession numbers followed by state abbreviation and collection year. (A) Nucletide alignment of 5′UTR. Compared with the Fermon strain, all circulating strains have a 23 nt deletion at position 681–703. The strains of lineage 1 have an additional 11 nt deletion at position 705 to 726. (B) Nucletide alignment of VP1. Compared with the Fermon strain, strains of lineage 2 had 3 nt have a deletion at position 2,806 to 2,808. (C) Phylogenetic analysis of all available EV-D68 strains based on complete genomes. The trees, with 1,000 bootstrap replicates, were generated by using the neighbor-joining algorithm in MEGA 4.0. The strain has only one deletion as indicated by black circles.

Fig. 4

World map depicting EV-D68 prevalence (country and year). Red indicates countries in which more than 1,000 cases have been detected, orange indicates countries in which 100 to 200 cases have been detected, and blue indicates countries in which less than100 cases have been detected.