Molecular and Clinical Comparison of Enterovirus D68 Outbreaks among Hospitalized Children, Ohio, USA, 2014 and 2018

Wang, Huanyu; Díaz, Alejandro; Moyer, Katherine; Mele-Casas, Maria; Ara-Montojo, Maria Fatima; Torrús, Isabel; McCoy, Karen D.; Mejías, Asunción; Leber, Amy

doi:10.3201/eid2511.190973

Cited by 24 publications

(35 citation statements)

References 35 publications

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“…Comparison between our and published data suggests considerable geographic and temporal variation in EV-D68 infection. First, studies in the United States noticed a widespread of EV-D68 cases in 2014 and 2018 but only low-level EV-D68 circulation in 2016 in some states, such as Colorado (15), Missouri (30), and Ohio (18). In contrast, we had a high percentage (24.5%) of patients with RhV/EV-positive NP specimens typed as EV-D68 in the Lower Hudson Valley, as well as the largest number of cases from a single health care facility in the United States in 2016.…”

Section: Resultsmentioning

confidence: 99%

“…Only 9 EV-D68 cases in 2015 and 138 EV-D68 cases in 2016 have been reported to the NESS (7). Similarly, a low level of EV-D68 circulation was evident in Colorado (15), Arizona (16), Washington (17), and Ohio (18) in 2016, where selective clinical specimens from patients with respiratory and neurological syndromes were investigated for EV-D68. In 2018, increased activity of EV-D68 was reported in Colorado (19), New York (20), and several U.S. states through the recently established CDC New Vaccine Surveillance Network (NVSN) (21).…”

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confidence: 99%

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Biennial Upsurge and Molecular Epidemiology of Enterovirus D68 Infection in New York, USA, 2014 to 2018

et al. 2020

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Enterovirus D68 (EV-D68) infection has been associated with outbreaks of severe respiratory illness and increased cases of non-polio acute flaccid myelitis. The patterns of EV-D68 circulation and molecular epidemiology are not fully understood. In this study nasopharyngeal (NP) specimens collected from patients in the Lower Hudson Valley, New York from 2014 to 2018 were examined for Rhinovirus/Enterovirus (RhV/EV) by the FilmArray Respiratory Panel. Selected RhV/EV-positive NP specimens were analyzed using two EV-D68-specific real-time RT-PCR assays, Sanger sequencing and metatranscriptomic next-generation sequencing. A total of 2,398 NP specimens were examined. EV-D68 was detected in 348 patients with NP specimens collected in 2014 (n=94), 2015 (n=0), 2016 (n=160), 2017 (n=5) and 2018 (n=89), demonstrating a biennial upsurge of EV-D68 infection in the study area. Ninety-one complete or nearly complete EV-D68 genome sequences were obtained. Genomic analysis of these EV-D68 strains revealed dynamics and evolution of circulating EV-D68 strains since 2014. The dominant EV-D68 strains causing the 2014 outbreak belonged to subclade B1, with a few belonging to subclade B2. New EV-D68 subclade B3 strains emerged in 2016 and continued in circulation in 2018. Clade D strains that are rarely detected in the US also arose and spread in 2018. The establishment of distinct viral strains and their variable circulation patterns provides essential information for future surveillance, diagnosis, vaccine development, and prediction of EV-D68-associated disease prevalence and potential outbreaks.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Biennial Upsurge and Molecular Epidemiology of Enterovirus D68 Infection in New York, USA, 2014 to 2018

et al. 2020

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“…In particular, from August 2014 to January 2015, a nationwide outbreak of EV-D68 infection occurred in the United States, resulting in 1,153 con rmed cases including 14 deaths 8,9 . EV-D68 outbreaks were also witnessed in the United States in 2016 and in 2018 10,11 , coinciding with the occurrence of 153 and 237 AFM cases, respectively 12 . In addition, an upsurge of EV-D68 infection was reported in several European countries in 2016 13,14,15 , accompanied by the identi cation of 29 EV-D68associated AFM cases 16 .…”

Section: Introductionmentioning

confidence: 92%

Development and structural characterization of a two-MAb cocktail for delayed treatment of enterovirus D68 infections

Huang

Zhang

et al. 2020

Preprint

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Enterovirus D68 (EV-D68) is an emerging pathogen associated with respiratory diseases and/or acute flaccid myelitis. Here, two MAbs, 2H12 and 8F12, raised against EV-D68 virus-like particle (VLP), showed distinct preference in binding VLP and virion and in neutralizing different strains. The 2H12/8F12 cocktail exhibited balanced and potent neutralization effects and conferred broader protection in mice than single MAbs when given at onset of symptoms. Cryo-EM structures of EV-D68 virion complexed with 2H12 or 8F12 showed that both antibodies bind to south rim of the canyon and obscure the canyon, blocking virus–cell binding. Additionally, 2H12 binding could partially impair virions and trigger uncoating, resulting in premature viral RNA release. We also captured an uncoating intermediate induced by 2H12 binding, not detected before in picornaviruses. Our study elucidates neutralizing mechanisms of the MAbs and supports further development of the 2H12/8F12 cocktail as a broad-spectrum therapeutic agent against EV-D68 infections in humans.

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“…Between 1970 and 2005, only 26 cases were reported to the CDC and the virus was generally associated with mild upper respiratory illness [8,9].In 2014, unprecedented outbreaks of EV-D68 associated with severe respiratory disease and acute flaccid myelitis emerged throughout the world [3,. Since 2014, there have been biannual patterns of severe disease associated with EV-D68 [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. This unique pattern of recurring outbreaks and severe pathology sheds light on the importance of understanding evolutionary changes in contemporary EV-D68 strains.…”

Section: Introductionmentioning

confidence: 99%

Contemporary Enterovirus D68 strains show enhanced replication and translation at 37°C

Smith

Pekosz

2020

Preprint

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Enterovirus D68 (EV-D68) emerged in 2014 as an important pathogen linked to severe lower respiratory disease and acute flaccid myelitis outbreaks. Historically associated with mild common-cold-like symptoms, clusters of severe disease attributed to EV-D68 appeared during a series of outbreaks in 2014, 2016, and 2018. Previous studies of historic EV-D68 strains demonstrated attenuated replication at temperatures of the lower respiratory tract (37°C), when compared to the upper respiratory tract (32°C). By testing a panel of historic and contemporary EV-D68 strains at 32°C and 37°C, we demonstrate that contemporary strains of EV-D68 undergo little to no attenuation at increased temperatures. Contemporary strains produced higher levels of viral proteins at 32°C and 37°C than historic strains, although both strains infected similar numbers of cells and had comparable amounts of replication complexes. IRES activity assays with dual-luciferase reporter plasmids demonstrated enhanced translation in recent EV-D68 strains mapped to regions of variability in the 5' UTR found only in contemporary strains. Using an infectious clone system, we demonstrate that the translation advantage dictated by the 5' UTR does not solely mediate temperature sensitivity. The strain-dependent effects of temperature on the EV-D68 life cycle gives insight into the susceptibility of the lower respiratory system to contemporary strains. IMPORTANCEEnterovirus-D68 (EV-D68) emerged in 2014 as a causative agent of biannual severe pediatric respiratory disease and acute flaccid myelitis (AFM). We show that recent EV-D68 viruses have gained the ability to replicate at 37⁰C. Enhanced virus protein translation seemed to correlate with enhanced virus replication at 37⁰C but other genetic factors are also contributing to this phenotype. An enhanced ability to replicate at core body temperature may have allowed EV-D68 to penetrate both lower in the respiratory tract and into the central nervous system, explaining the recent surge in severe disease associated with virus infection.

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Molecular and Clinical Comparison of Enterovirus D68 Outbreaks among Hospitalized Children, Ohio, USA, 2014 and 2018

Cited by 24 publications

References 35 publications

Biennial Upsurge and Molecular Epidemiology of Enterovirus D68 Infection in New York, USA, 2014 to 2018

Biennial Upsurge and Molecular Epidemiology of Enterovirus D68 Infection in New York, USA, 2014 to 2018

Development and structural characterization of a two-MAb cocktail for delayed treatment of enterovirus D68 infections

Contemporary Enterovirus D68 strains show enhanced replication and translation at 37°C

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