Epidemiological and Clinical Insights into the Enterovirus D68 Upsurge in Europe 2021-2022 and Emergence of Novel B3-Derived Lineages, ENPEN Multicentre Study

Abstract

Enterovirus D68 (EV-D68) infections are associated with severe respiratory disease and acute flaccid myelitis (AFM). The European Non-Polio Enterovirus Network (ENPEN) aimed to investigate the epidemiological and genetic characteristics of EV-D68 infections and its clinical impact during the fall-winter season of 2021-2022. From 19 European countries, 58 institutes reported 10 481 (6.8%) EV-positive samples of which 1004 (9.6%) were identified as EV-D68 (including 852 respiratory samples). Clinical data were reported for 969 cases; 78.9% of infections were reported in children (0-5 years); and 37.9% of cases were hospitalized. Acute respiratory distress was commonly noted (93.1%) followed by fever (49.4%). Neurological problems were observed in 6.4% of cases including 6 diagnosed with AFM. Phylodynamic/Nextstrain and phylogenetic analyses based on 694 sequences showed the emergence of 2 novel B3-derived lineages, with no regional clustering. In conclusion, we describe a large-scale European EV-D68 upsurge with severe clinical impact and the emergence of B3-derived lineages.

Keywords: European Non-Polio Enterovirus Network (ENPEN); acute flaccid myelitis (AFM); enterovirus D68 (EV-D68); nonpolio enterovirus (NPEV); respiratory infection.

Figure 1.

Diagram of the information collected: epidemiological data, clinical records, and sequence data with associated clinical metadata used for the analysis of the EV-D68 upsurge in Europe, 2021–2022. Sequence information is also represented separately for phylogenetic reconstruction (Nextstrain analysis) and divergence analysis. Publicly accessible sequences, extracted from Gen Bank, used for epidemiologic analysis are depicted in boxes alongside exclusion criteria. *Monthly testing data were received from 55 institutes, 18 countries; and monthly EV-positive data received from 57 institutes, 19 countries. #Two institutes only reported EV-D68 cases for 2022 (1 also representing the country cases).

Figure 2.

Proportion of samples found positive for EV (lined bars, % of EV-positive samples/number of samples tested) and EV-D68 (grey bars, % of EV-D68–positive samples/number of EV positive samples), and monthly totals of EV tests (line) reveal an increasing trend from September 2021 onwards. The highest numbers of EV and EV-D68 detections were observed in October 2021.

Figure 3.

A–C, Phylodynamic analysis of EV-D68 with Nextstrain using 692 partial study VP1 sequences > 300 bp and 3307 publicly available VP1 sequences. B and C, Zoomed views of areas of the tree containing the 2 novel lineages. D, Neighbor-joining phylogenetic tree of complete genome from the study samples (n = 82) and 1025 sequences with data annotations from GenBank. E, Neighbor-joining phylogenetic tree of VP1 region sequences (positions 2501–2842, numbered using the Fermon prototype sequence, KU844179) from the study samples (n = 559) and 3306 sequences with data annotations from GenBank.

Figure 4.

Maps showing the geographic distribution of the 2 novel EV-D68 B3-derived lineages, lineage 1 (A) and lineage 2 (B).