Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role

Jolene R. Bowers, Michael Valentine, Veronica Harrison, Viacheslav Y. Fofanov, John Gillece, Josie Delisle, Bethany Patton, James Schupp, Krystal Sheridan, Darrin Lemmer, Scott Ostdiek, Harlori K. Bains, Jennifer Heim, Tammy Sylvester, Siru Prasai, Melissa Kretschmer, Nicole Fowle, Kenneth Komatsu, Shane Brady, Susan Robinson & 7 others Kathryn Fitzpatrick, Gholamabbas Amin Ostovar, Eric Alsop, Elizabeth Hutchins, Kendall Jensen, Paul S Keim, David M. Engelthaler

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
JournalmBio
Volume10
Issue number1
DOIs
StatePublished - Jan 22 2019

Fingerprint

Myelitis
Enterovirus
Poliovirus
Metagenomics
Nervous System Diseases
Cerebrospinal Fluid
Real-Time Polymerase Chain Reaction
Acute Disseminated Encephalomyelitis
Pediatrics
Herpes Simplex
Herpesviridae
RNA Viruses
Microbiota
Viral DNA
Virus Diseases

Keywords

  • acute flaccid myelitis
  • AFM
  • enterovirus
  • EV-D68
  • genomics
  • metagenomics

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Bowers, J. R., Valentine, M., Harrison, V., Fofanov, V. Y., Gillece, J., Delisle, J., ... 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

Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role. / Bowers, Jolene R.; Valentine, Michael; Harrison, Veronica; Fofanov, Viacheslav Y.; Gillece, John; Delisle, Josie; Patton, Bethany; Schupp, James; Sheridan, Krystal; Lemmer, Darrin; Ostdiek, Scott; Bains, Harlori K.; Heim, Jennifer; Sylvester, Tammy; Prasai, Siru; Kretschmer, Melissa; Fowle, Nicole; Komatsu, Kenneth; Brady, Shane; Robinson, Susan; Fitzpatrick, Kathryn; Ostovar, Gholamabbas Amin; Alsop, Eric; Hutchins, Elizabeth; Jensen, Kendall; Keim, Paul S; Engelthaler, David M.

In: mBio, Vol. 10, No. 1, 22.01.2019.

Research output: Contribution to journalArticle

Bowers, JR, Valentine, M, Harrison, V, Fofanov, VY, Gillece, J, Delisle, J, Patton, B, Schupp, J, Sheridan, K, Lemmer, D, Ostdiek, S, Bains, HK, Heim, J, Sylvester, T, Prasai, S, Kretschmer, M, Fowle, N, Komatsu, K, Brady, S, Robinson, S, Fitzpatrick, K, Ostovar, GA, Alsop, E, Hutchins, E, Jensen, K, Keim, PS & Engelthaler, DM 2019, 'Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role', mBio, vol. 10, no. 1. https://doi.org/10.1128/mBio.02262-18
Bowers, Jolene R. ; Valentine, Michael ; Harrison, Veronica ; Fofanov, Viacheslav Y. ; Gillece, John ; Delisle, Josie ; Patton, Bethany ; Schupp, James ; Sheridan, Krystal ; Lemmer, Darrin ; Ostdiek, Scott ; Bains, Harlori K. ; Heim, Jennifer ; Sylvester, Tammy ; Prasai, Siru ; Kretschmer, Melissa ; Fowle, Nicole ; Komatsu, Kenneth ; Brady, Shane ; Robinson, Susan ; Fitzpatrick, Kathryn ; Ostovar, Gholamabbas Amin ; Alsop, Eric ; Hutchins, Elizabeth ; Jensen, Kendall ; Keim, Paul S ; Engelthaler, David M. / Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role. In: mBio. 2019 ; Vol. 10, No. 1.
@article{0cb962402756467da0ea55deac53c4f7,
title = "Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role",
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.",
keywords = "acute flaccid myelitis, AFM, enterovirus, EV-D68, genomics, metagenomics",
author = "Bowers, {Jolene R.} and Michael Valentine and Veronica Harrison and Fofanov, {Viacheslav Y.} and John Gillece and Josie Delisle and Bethany Patton and James Schupp and Krystal Sheridan and Darrin Lemmer and Scott Ostdiek and Bains, {Harlori K.} and Jennifer Heim and Tammy Sylvester and Siru Prasai and Melissa Kretschmer and Nicole Fowle and Kenneth Komatsu and Shane Brady and Susan Robinson and Kathryn Fitzpatrick and Ostovar, {Gholamabbas Amin} and Eric Alsop and Elizabeth Hutchins and Kendall Jensen and Keim, {Paul S} and Engelthaler, {David M.}",
year = "2019",
month = "1",
day = "22",
doi = "10.1128/mBio.02262-18",
language = "English (US)",
volume = "10",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "1",

}

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 S

AU - Engelthaler, David M.

PY - 2019/1/22

Y1 - 2019/1/22

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.

AB - 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.

KW - acute flaccid myelitis

KW - AFM

KW - enterovirus

KW - EV-D68

KW - genomics

KW - metagenomics

UR - http://www.scopus.com/inward/record.url?scp=85060370356&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060370356&partnerID=8YFLogxK

U2 - 10.1128/mBio.02262-18

DO - 10.1128/mBio.02262-18

M3 - Article

VL - 10

JO - mBio

JF - mBio

SN - 2161-2129

IS - 1

ER -