Enterovirus D68 epidemic, UK, 2018, was caused by subclades B3 and D1, predominantly in children and adults, respectively, with both subclades exhibiting extensive genetic diversity
Enterovirus D68 (EV-D68) has recently been identified in biennial epidemics coinciding with diagnoses of non-polio acute flaccid paralysis/myelitis (AFP/AFM). We investigated the prevalence, genetic relatedness and associated clinical features of EV-D68 in 193 EV-positive samples from 193 patients in late 2018, UK. EV-D68 was detected in 83 (58 %) of 143 confirmed EV-positive samples. Sequencing and phylogenetic analysis revealed extensive genetic diversity, split between subclades B3 (n=50) and D1 (n=33), suggesting epidemiologically unrelated infections. B3 predominated in children and younger adults, and D1 in older adults and the elderly (P=0.0009). Clinical presentation indicated causation or exacerbation of respiratory distress in 91.4 % of EV-D68-positive individuals, principally cough (75.3 %), shortness of breath (56.8 %), coryza (48.1 %), wheeze (46.9 %), supplemental oxygen required (46.9 %) and fever (38.9 %). Two cases of AFM were observed, one with EV-D68 detectable in the cerebrospinal fluid, but otherwise neurological symptoms were rarely reported (n=4). Both AFM cases and all additional instances of intensive care unit (ICU) admission (n=5) were seen in patients infected with EV-D68 subclade B3. However, due to the infrequency of severe infection in our cohort, statistical significance could not be assessed.
This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
SimmondsP, GorbalenyaAE, HarvalaH, HoviT, KnowlesNJ et al. Recommendations for the nomenclature of enteroviruses and rhinoviruses. Arch Virol2020; 165:793–797 [View Article] [PubMed]
BubbaL, BrobergEK, JasirA, SimmondsP, HarvalaH et al. Circulation of non-polio enteroviruses in 24 EU and EEA countries between 2015 and 2017: a retrospective surveillance study. Lancet Infect Dis2020; 20:350–361 [View Article] [PubMed]
Pons-SalortM, GrasslyNC. Serotype-specific immunity explains the incidence of diseases caused by human enteroviruses. Science2018; 361:800–803 [View Article] [PubMed]
GreningerAL, NaccacheSN, MessacarK, ClaytonA, YuG et al. A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-14): A retrospective cohort study. Lancet Infect Dis2015; 15:671–682 [View Article] [PubMed]
EshaghiA, DuvvuriVR, IsabelS, BanhP, LiA et al. Global distribution and evolutionary history of enterovirus D68, with emphasis on the 2014 outbreak in Ontario, Canada. Front Microbiol2017; 8:257 [View Article] [PubMed]
MessacarK, SchreinerTL, MaloneyJA, WallaceA, LudkeJ et al. A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA. Lancet2015; 385:1662–1671 [View Article] [PubMed]
KirolosA, MarkK, ShettyJ, ChinchankarN, McdougallC et al. Outcome of paediatric acute flaccid myelitis associated with enterovirus D68: a case series. Dev Med Child Neurol2019; 61:376–380 [View Article] [PubMed]
LauSKP, YipCCY, ZhaoPS-H, ChowW-N, ToKKW et al. Enterovirus D68 Infections Associated with Severe Respiratory Illness in Elderly Patients and Emergence of a Novel Clade in Hong Kong. Sci Rep2016; 6:25147 [View Article] [PubMed]
GongY-N, YangS-L, ShihS-R, HuangY-C, ChangP-Y et al. Molecular evolution and the global reemergence of enterovirus D68 by genome-wide analysis. Medicine (Baltimore)2016; 95:e4416 [View Article] [PubMed]
BrownDM, HixonAM, OldfieldLM, ZhangY, NovotnyM et al. Contemporary circulating enterovirus D68 strains have acquired the capacity for viral entry and replication in human neuronal cells. mBio2018; 9:e01954-18 [View Article] [PubMed]
HixonAM, YuG, LeserJS, YagiS, ClarkeP et al. A mouse model of paralytic myelitis caused by enterovirus D68. PLoS Pathog2017; 13:e1006199 [View Article] [PubMed]
ZhangC, ZhangX, DaiW, LiuQ, XiongP et al. A mouse model of enterovirus D68 infection for assessment of the efficacy of inactivated vaccine. Viruses2018; 10:E58 [View Article] [PubMed]
RosenfeldAB, WarrenAL, RacanielloVR. Neurotropism of enterovirus D68 isolates is independent of sialic acid and is not a recently acquired phenotype. mBio2019; 10:e02370-19 [View Article] [PubMed]
ObersteMS, MaherK, SchnurrD, FlemisterMR, LovchikJC et al. Enterovirus 68 is associated with respiratory illness and shares biological features with both the enteroviruses and the rhinoviruses. J Gen Virol2004; 85:2577–2584 [View Article] [PubMed]
MidgleySE, BenschopK, DyrdakR, MirandA, BaillyJ-L et al. Co-circulation of multiple enterovirus D68 subclades, including a novel B3 cluster, across Europe in a season of expected low prevalence, 2019/20. Euro Surveill2020; 25: [View Article] [PubMed]
PellegrinelliL, GiardinaF, LunghiG, Uceda RenteriaSC, GrecoL et al. Emergence of divergent enterovirus (EV) D68 sub-clade D1 strains, northern Italy, September to October 2018. Euro Surveill2019; 24: [View Article] [PubMed]
BalA, SabatierM, WirthT, Coste-BurelM, LazrekM et al. Emergence of enterovirus D68 clade D1, France, August to November 2018. Euro Surveill2019; 24: [View Article]
KramerR, SabatierM, WirthT, PichonM, LinaB et al. Molecular diversity and biennial circulation of enterovirus D68: a systematic screening study in Lyon, France, 2010 to 2016. Euro Surveill2018; 23: [View Article]
PirallaA, PrincipiN, RuggieroL, GirelloA, GiardinaF et al. Enterovirus-D68 (EV-D68) in pediatric patients with respiratory infection: The circulation of a new B3 clade in Italy. J Clin Virol2018; 99–100:91–96 [View Article] [PubMed]
DuvalM, MirandA, LesensO, BayJ-O, CaillaudD et al. Retrospective study of the upsurge of enterovirus D68 clade D1 among adults (2014-2018). Viruses2021; 13:1607 [View Article] [PubMed]
KamauE, HarvalaH, BlomqvistS, NguyenD, HorbyP et al. Increase in enterovirus D68 infections in young children, United Kingdom, 2006-2016. Emerg Infect Dis2019; 25:1200–1203 [View Article] [PubMed]
HarrisonCJ, WeldonWC, PahudBA, JacksonMA, ObersteMS et al. Neutralizing antibody against enterovirus D68 in children and adults before 2014 outbreak, Kansas City, Missouri, USA1. Emerg Infect Dis2019; 25:585–588 [View Article]
MishraN, NgTFF, MarineRL, JainK, NgJ et al. Antibodies to enteroviruses in cerebrospinal fluid of patients with acute flaccid myelitis. mBio2019; 10:e01903-19 [View Article] [PubMed]
HarvalaH, BrobergE, BenschopK, BergincN, LadhaniS et al. Recommendations for enterovirus diagnostics and characterisation within and beyond Europe. J Clin Virol2018; 101:11–17 [View Article] [PubMed]
BowersJR, ValentineM, HarrisonV, FofanovVY, GilleceJ et al. Genomic analyses of acute flaccid myelitis cases among a cluster in Arizona provide further evidence of enterovirus D68 role. mBio2019; 10:e02262-18 [View Article] [PubMed]
WangH, DiazA, MoyerK, Mele-CasasM, Ara-MontojoMF et al. Molecular and clinical comparison of enterovirus D68 outbreaks among hospitalized children, Ohio, USA, 2014 and 2018. Emerg Infect Dis2019; 25:2055–2063 [View Article] [PubMed]
NixWA, ObersteMS, PallanschMA. Sensitive, seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol2006; 44:2698–2704 [View Article] [PubMed]
SimmondsP, WelchJ. Frequency and dynamics of recombination within different species of human enteroviruses. J Virol2006; 80:483–493 [View Article] [PubMed]
Howson-WellsHC, WincklesS, AlikerC, TarrAW, IrvingWL et al. Enterovirus subtyping in a routine UK laboratory setting between 2013 and 2017. J Clin Virol2020; 132:104646 [View Article] [PubMed]
MinhBQ, SchmidtHA, ChernomorO, SchrempfD, WoodhamsMD et al. IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era. Mol Biol Evol2020; 37:1530–1534 [View Article] [PubMed]
TangS-H, YuanY, XieZ-H, ChenM-J, FanX-D et al. Enterovirus D68 in hospitalized children with respiratory symptoms in Guangdong from 2014 to 2018: Molecular epidemiology and clinical characteristics. J Clin Virol2021; 141:104880 [View Article] [PubMed]
FischerTK, SimmondsP, HarvalaH. The importance of enterovirus surveillance in a post-polio world. Lancet Infect Dis2022; 22:e35–e40 [View Article] [PubMed]
Carrion MartinAI, PebodyRG, DanisK, EllisJ, NiaziS et al. The emergence of enterovirus D68 in England in autumn 2014 and the necessity for reinforcing enterovirus respiratory screening. Epidemiol Infect2017; 145:1855–1864 [View Article] [PubMed]
ParkSW, Pons-SalortM, MessacarK, CookC, MeyersL et al. Epidemiological dynamics of enterovirus D68 in the United States and implications for acute flaccid myelitis. Sci Transl Med2021; 13:eabd2400 [View Article] [PubMed]
The United Kingdom Acute Flaccid Paralysis Afp Task Force An increase in reports of acute flaccid paralysis (AFP) in the United Kingdom, 1 January 2018-21 January 2019: early findings. Euro Surveill2019; 24: [View Article]
CottrellS, MooreC, PerryM, HilversE, WilliamsC et al. Prospective enterovirus D68 (EV-D68) surveillance from September 2015 to November 2018 indicates a current wave of activity in Wales. Euro Surveill2018; 23: [View Article] [PubMed]
HayesA, NguyenD, AnderssonM, AntonA, BaillyJL et al. A European multicentre evaluation of detection and typing methods for human enteroviruses and parechoviruses using RNA transcripts. J Med Virol2019
HodcroftEB, DyrdakR, AndrésC, EgliA, ReistJ et al. Evolution, geographic spreading, and demographic distribution of Enterovirus D68. Microbiology2020 [View Article]
VieiraMC, DonatoCM, ArevaloP, RimmelzwaanGF, WoodT et al. Lineage-specific protection and immune imprinting shape the age distributions of influenza B cases. Nat Commun2021; 12:4313 [View Article] [PubMed]
KaidaA, IritaniN, YamamotoSP, KanbayashiD, HiraiY et al. Distinct genetic clades of enterovirus D68 detected in 2010, 2013, and 2015 in Osaka City, Japan. PLoS One2017; 12:e0184335 [View Article] [PubMed]
ZhangY, CaoJ, ZhangS, LeeAJ, SunG et al. Genetic changes found in a distinct clade of Enterovirus D68 associated with paralysis during the 2014 outbreak. Virus Evol2016; 2:vew015 [View Article] [PubMed]
ChongPF, KiraR, MoriH, OkumuraA, TorisuH et al. Clinical features of acute flaccid myelitis temporally associated with an enterovirus D68 outbreak: results of a nationwide survey of acute flaccid paralysis in Japan, August-December 2015. Clin Infect Dis2018; 66:653–664 [View Article] [PubMed]
MajumdarM, MartinJ. Detection by direct next generation sequencing analysis of emerging enterovirus D68 and C109 strains in an environmental sample from Scotland. Front Microbiol2018; 9:1956 [View Article] [PubMed]
WeilM, MandelboimM, MendelsonE, ManorY, ShulmanL et al. Human enterovirus D68 in clinical and sewage samples in Israel. J Clin Virol2017; 86:52–55 [View Article] [PubMed]
Enterovirus D68 epidemic, UK, 2018, was caused by subclades B3 and D1, predominantly in children and adults, respectively, with both subclades exhibiting extensive genetic diversity