Clade-specific transmission dynamics of enterovirus D68 and their association with acute flaccid myelitis

Enterovirus D68 (EV-D68) is a common cause of mild respiratory illness in children but is also linked to acute flaccid myelitis (AFM), a rare and severe neurological condition which can result in permanent paralysis. Tracking EV-D68 transmission is difficult because symptoms overlap with other common childhood illnesses, making case reporting unreliable. As a result, the burden of EV-D68 transmission remains poorly understood, particularly prior to the first widely recognised outbreak in 2014. Phylodynamic approaches offer a powerful alternative to case-based surveillance, inferring epidemiological parameters directly from pathogen genetic sequences. Here we show, using a birth-death-sampling phylodynamic model applied to publicly available EV-D68 sequences from the 1990s to 2023 collected in Europe and North America, that seasonal EV-D68 transmission was well established long before the 2014 outbreak brought the virus to widespread attention. Furthermore, we show that AFM case burden is strongly associated with the transmission dynamics of a specific EV-D68 clade, clade B, an association not seen for clades A and D. These findings suggest that clade-specific biological differences drive AFM risk, with important implications for surveillance prioritisation and the timing of future burden of neurological disease.