Enterovirus D68 (EV-D68) is a small, non-enveloped, positive-sense, single-stranded RNA virus belonging to the species Enterovirus D within the genus Enterovirus, family Picornaviridae. First isolated in California in 1962 from children with respiratory illness, EV-D68 was for decades considered a rare cause of infection, detected only sporadically, before emerging as a significant global public health concern following a large outbreak of severe respiratory disease across the United States in 2014. Unlike most enteroviruses, which are transmitted by the faecal-oral route and preferentially infect the gastrointestinal tract, EV-D68 shares biological and clinical features with rhinoviruses, spreading predominantly via the respiratory route, and associated primarily with respiratory rather than enteric disease.

The EV-D68 virion is a small, icosahedral particle approximately 30 nanometres in diameter, composed of a protein capsid built from sixty copies each of four structural proteins, VP1, VP2, VP3, and VP4, surrounding a genome of roughly 7,400 nucleotides. The genome contains a single open reading frame flanked by structured untranslated regions, with translation initiated internally via an internal ribosome entry site in the 5′ untranslated region. The genome is translated as a single polyprotein that is co- and post-translationally cleaved by the virally encoded 2A and 3C proteases into the structural P1 proteins, which form the capsid, and the non-structural P2 and P3 proteins, which include the 3D RNA-dependent RNA polymerase responsible for genome replication and the 2C protein involved in remodelling host membranes to form replication organelles. Cell entry is mediated by attachment to sialylated glycan receptors on the surface of respiratory epithelial cells.

Molecular epidemiological surveillance has identified several genetically distinct EV-D68 clades and subclades, designated A, B, C, and D, with further subdivision (for example B1, B3, A2), which circulate and turn over globally in a manner reminiscent of influenza virus evolution, and which are used to track transmission chains and outbreak dynamics.

EV-D68 infection typically causes mild to moderate upper respiratory symptoms, including cough, and fever, but can progress to severe lower respiratory tract disease, including bronchiolitis and pneumonia, particularly in infants, young children, and individuals with pre-existing asthma or other chronic respiratory conditions. Since 2014, EV-D68 outbreaks have recurred in a broadly biennial pattern in many countries, coinciding with clusters of acute flaccid myelitis (AFM), a rare but serious neurological condition characterised by sudden onset of limb weakness resulting from damage to the anterior horn cells of the spinal cord. Although a definitive mechanistic link has been challenging to establish, epidemiological, clinical, and immunological evidence, including detection of EV-D68 in respiratory and, less consistently, cerebrospinal specimens of affected children, together with the temporal association between EV-D68 circulation and AFM clusters, strongly implicates the virus as a leading cause of paediatric AFM.

There is currently no licensed vaccine or antiviral therapy specific to EV-D68, and clinical management remains supportive. The public health significance of the virus, combined with its capacity for rapid antigenic and genetic change, has driven active research into candidate vaccines, capsid-binding and protease-targeted antivirals, and improved diagnostic and surveillance tools, alongside efforts to better define the mechanisms by which the virus gains access to and damages the central nervous system.