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Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role.
mBio. 2019 01 22; 10(1)MBIO

Abstract

Enteroviruses are a common cause of respiratory and gastrointestinal illness, and multiple subtypes, including poliovirus, can cause neurologic disease. In recent years, enterovirus D68 (EV-D68) has been associated with serious neurologic illnesses, including acute flaccid myelitis (AFM), frequently preceded by respiratory disease. A cluster of 11 suspect cases of pediatric AFM was identified in September 2016 in Phoenix, AZ. To determine if these cases were associated with EV-D68, we performed multiple genomic analyses of nasopharyngeal (NP) swabs and cerebrospinal fluid (CSF) material from the patients, including real-time PCR and amplicon sequencing targeting the EV-D68 VP1 gene and unbiased microbiome and metagenomic sequencing. Four of the 11 patients were classified as confirmed cases of AFM, and an additional case was classified as probable AFM. Real-time PCR and amplicon sequencing detected EV-D68 virus RNA in the three AFM patients from which NP swabs were collected, as well as in a fourth patient diagnosed with acute disseminated encephalomyelitis, a disease that commonly follows bacterial or viral infections, including enterovirus. No other obvious etiological causes for AFM were identified by 16S or RNA and DNA metagenomic sequencing in these cases, strengthening the likelihood that EV-D68 is an etiological factor. Herpes simplex viral DNA was detected in the CSF of the fourth case of AFM and in one additional suspect case from the cluster. Multiple genomic techniques, such as those described here, can be used to diagnose patients with suspected EV-D68 respiratory illness, to aid in AFM diagnosis, and for future EV-D68 surveillance and epidemiology.IMPORTANCE Enteroviruses frequently result in respiratory and gastrointestinal illness; however, multiple subtypes, including poliovirus, can cause severe neurologic disease. Recent biennial increases (i.e., 2014, 2016, and 2018) in cases of non-polio acute flaccid paralysis have led to speculations that other enteroviruses, specifically enterovirus D68 (EV-D68), are emerging to fill the niche that was left from poliovirus eradication. A cluster of 11 suspect cases of pediatric acute flaccid myelitis (AFM) was identified in 2016 in Phoenix, AZ. Multiple genomic analyses identified the presence of EV-D68 in the majority of clinical AFM cases. Beyond limited detection of herpesvirus, no other likely etiologies were found in the cluster. These findings strengthen the likelihood that EV-D68 is a cause of AFM and show that the rapid molecular assays developed for this study are useful for investigations of AFM and EV-D68.

Authors+Show Affiliations

Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.School of Informatics Computing and Cyber Systems, Northern Arizona University, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.Phoenix Children's Hospital, Phoenix, Arizona, USA.Phoenix Children's Hospital, Phoenix, Arizona, USA.Phoenix Children's Hospital, Phoenix, Arizona, USA.Maricopa County Department of Public Health, Phoenix, Arizona, USA.Maricopa County Department of Public Health, Phoenix, Arizona, USA.Maricopa County Department of Public Health, Phoenix, Arizona, USA.Maricopa County Department of Public Health, Phoenix, Arizona, USA.Arizona Department of Health Services, Phoenix, Arizona, USA.Arizona Department of Health Services, Phoenix, Arizona, USA.Arizona Department of Health Services, Phoenix, Arizona, USA.Arizona Department of Health Services, Phoenix, Arizona, USA.Maricopa Integrated Health System, Phoenix, Arizona, USA.Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA.Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA.Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA. Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA.Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA dengelthaler@tgen.org.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

30670612

Citation

Bowers, Jolene R., et al. "Genomic Analyses of Acute Flaccid Myelitis Cases Among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role." MBio, vol. 10, no. 1, 2019.
Bowers JR, Valentine M, Harrison V, et al. Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role. mBio. 2019;10(1).
Bowers, J. R., Valentine, M., Harrison, V., Fofanov, V. Y., Gillece, J., Delisle, J., Patton, B., Schupp, J., Sheridan, K., Lemmer, D., Ostdiek, S., Bains, H. K., Heim, J., Sylvester, T., Prasai, S., Kretschmer, M., Fowle, N., Komatsu, K., Brady, S., ... Engelthaler, D. M. (2019). Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role. MBio, 10(1). https://doi.org/10.1128/mBio.02262-18
Bowers JR, et al. Genomic Analyses of Acute Flaccid Myelitis Cases Among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role. mBio. 2019 01 22;10(1) PubMed PMID: 30670612.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role. AU - Bowers,Jolene R, AU - Valentine,Michael, AU - Harrison,Veronica, AU - Fofanov,Viacheslav Y, AU - Gillece,John, AU - Delisle,Josie, AU - Patton,Bethany, AU - Schupp,James, AU - Sheridan,Krystal, AU - Lemmer,Darrin, AU - Ostdiek,Scott, AU - Bains,Harlori K, AU - Heim,Jennifer, AU - Sylvester,Tammy, AU - Prasai,Siru, AU - Kretschmer,Melissa, AU - Fowle,Nicole, AU - Komatsu,Kenneth, AU - Brady,Shane, AU - Robinson,Susan, AU - Fitzpatrick,Kathryn, AU - Ostovar,Gholamabbas Amin, AU - Alsop,Eric, AU - Hutchins,Elizabeth, AU - Jensen,Kendall, AU - Keim,Paul, AU - Engelthaler,David M, Y1 - 2019/01/22/ PY - 2019/1/24/entrez PY - 2019/1/24/pubmed PY - 2019/4/6/medline KW - AFM KW - EV-D68 KW - acute flaccid myelitis KW - enterovirus KW - genomics KW - metagenomics JF - mBio JO - mBio VL - 10 IS - 1 N2 - Enteroviruses are a common cause of respiratory and gastrointestinal illness, and multiple subtypes, including poliovirus, can cause neurologic disease. In recent years, enterovirus D68 (EV-D68) has been associated with serious neurologic illnesses, including acute flaccid myelitis (AFM), frequently preceded by respiratory disease. A cluster of 11 suspect cases of pediatric AFM was identified in September 2016 in Phoenix, AZ. To determine if these cases were associated with EV-D68, we performed multiple genomic analyses of nasopharyngeal (NP) swabs and cerebrospinal fluid (CSF) material from the patients, including real-time PCR and amplicon sequencing targeting the EV-D68 VP1 gene and unbiased microbiome and metagenomic sequencing. Four of the 11 patients were classified as confirmed cases of AFM, and an additional case was classified as probable AFM. Real-time PCR and amplicon sequencing detected EV-D68 virus RNA in the three AFM patients from which NP swabs were collected, as well as in a fourth patient diagnosed with acute disseminated encephalomyelitis, a disease that commonly follows bacterial or viral infections, including enterovirus. No other obvious etiological causes for AFM were identified by 16S or RNA and DNA metagenomic sequencing in these cases, strengthening the likelihood that EV-D68 is an etiological factor. Herpes simplex viral DNA was detected in the CSF of the fourth case of AFM and in one additional suspect case from the cluster. Multiple genomic techniques, such as those described here, can be used to diagnose patients with suspected EV-D68 respiratory illness, to aid in AFM diagnosis, and for future EV-D68 surveillance and epidemiology.IMPORTANCE Enteroviruses frequently result in respiratory and gastrointestinal illness; however, multiple subtypes, including poliovirus, can cause severe neurologic disease. Recent biennial increases (i.e., 2014, 2016, and 2018) in cases of non-polio acute flaccid paralysis have led to speculations that other enteroviruses, specifically enterovirus D68 (EV-D68), are emerging to fill the niche that was left from poliovirus eradication. A cluster of 11 suspect cases of pediatric acute flaccid myelitis (AFM) was identified in 2016 in Phoenix, AZ. Multiple genomic analyses identified the presence of EV-D68 in the majority of clinical AFM cases. Beyond limited detection of herpesvirus, no other likely etiologies were found in the cluster. These findings strengthen the likelihood that EV-D68 is a cause of AFM and show that the rapid molecular assays developed for this study are useful for investigations of AFM and EV-D68. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/30670612/Genomic_Analyses_of_Acute_Flaccid_Myelitis_Cases_among_a_Cluster_in_Arizona_Provide_Further_Evidence_of_Enterovirus_D68_Role_ L2 - http://mbio.asm.org/cgi/pmidlookup?view=long&pmid=30670612 DB - PRIME DP - Unbound Medicine ER -