Enterovirus D68: Genomic and Clinical Comparison of 2 Seasons of Increased Viral Circulation and Discrepant Incidence of Acute Flaccid Myelitis-Maryland, USA.

Background: Enterovirus D68 (EV-D68) is associated with severe respiratory disease and acute flaccid myelitis (AFM). The 2022 outbreaks showed increased viral circulation and hospital admissions, but the expected rise in AFM cases did not occur. We analyzed EV-D68 genomes and infection outcomes from 2022 (a year without a national increase in AFM cases) and 2018 (a year with a national surge in AFM cases) to understand how viral genomic changes might influence disease outcomes.

Methods: Residual respiratory samples that tested positive for rhinovirus/enterovirus at the Johns Hopkins Health System between 2018 and 2022 were collected for EV-D68 polymerase chain reaction, genotyping, and whole genome sequencing. Clinical and metadata were collected in bulk from the electronic medical records.

Results: A total of 351 EV-D68 cases were identified, with most cases in children aged <5 years. Infections in 2018 were associated with higher odds of hospital admissions and intensive care unit care. Of 272 EV-D68 genomes, subclades B3 and A2/D1 were identified with B3 predominance (95.2%). A comparative analysis of the 2018 and 2022 whole genomes identified a cluster of amino acids (554D, 650T, 918T, 945N, 1445I, 1943I) that was associated with higher odds of severe outcomes.

Conclusions: Our results show significant differences in the clinical outcomes of EV-D68 infections in 2018 and 2022 and highlight a 2018 cluster of genomic changes associated with these differences. Seasonal viral genomic surveillance-with in vitro characterization of the significance of these changes to viral fitness, immune responses, and neuropathogenesis-should shed light on the viral determinants of AFM.