Epidemiological and Clinical Characteristics of the Enterovirus D68 Outbreak in Spain in 2024

Enterovirus D68 (EV‐D68) is a significant cause of respiratory and neurological disease worldwide. In 2024, Spain experienced its largest recorded EV‐D68 outbreak, accounting for 37.4% of all typed EV (294/892). This study describes the epidemiological, clinical, and phylogenetic features of EV‐D68 infections. Unexpectedly, EV‐D68 infections as it seems were more frequent in adults than in children (57.2% vs. 42.8%, p < 0.05), particularly among individuals > 60 years (38.6%). In 84.9% of cases with an EV‐D68 infection, EV‐D68 was the sole pathogen detected. Respiratory pathologies predominated (91.9%), with bronchospasm/wheezing episodes and bronchiolitis in children, and pneumonia and exacerbations of chronic obstructive pulmonary disease in older adults ( p < 0.05). Older patients showed a more severe clinical profile than pediatric patients, including higher hospitalization rates (79% vs. 59%), longer hospital stays (mean, 10.8 vs. 4.9 days), and more comorbidities (50% vs. 31%) ( p < 0.01). Phylogenetic analysis revealed two co‐circulating lineages with distinct age‐related tropisms: B3.3 mainly affected children (88.5%), whereas the novel A2/D1.1 infected adults predominantly (79.6%), particularly ≥ 60 years (49.5%) ( p < 0.05). This pattern may reflect lineage‐specific amino acid substitutions enhancing immune evasion. Neurological disease occurred in only three patients > 60 years infected by the A2/D1.1 lineage, which contained neurovirulent substitutions (I553L, K835E, and T860N). Results support continued genomic and clinical surveillance of EV‐D68.