Enterovirus D68 in the Anterior Horn Cells of a Child with Acute Flaccid Myelitis

Vogt, Matthew R.; Wright, Peter F.; Hickey, William F.; Buysscher, Tristan De; Boyd, Kelli L.; Crowe, James E.

doi:10.1056/nejmc2118155

Cited by 28 publications

(25 citation statements)

References 6 publications

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“…Enterovirus D68 (EV-D68; genus Enterovirus, family Picornaviridae) can cause severe respiratory illness, with clinical manifestations that include bronchiolitis, wheezing, and pneumonia, especially in children (1). EV-D68 has also been associated with acute flaccid myelitis (2)(3)(4)(5). EV-D68 had been relatively rare from its discovery in 1962 until the mid-2000s (6) but more recently, it has been associated with clusters and outbreaks of severe respiratory disease worldwide (2,7,8) .…”

Section: Introductionmentioning

confidence: 99%

Type-specific EV-D68 real-time RT-PCR assay for the detection of all extant enterovirus D68 strains

Ng¹,

Nix²,

Rogers³

et al. 2022

Preprint

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Enterovirus D68 (EV-D68) has caused recurring respiratory disease outbreaks in the United States since 2014. The dominant circulating EV-D68 strain has evolved from clade B1 to the more recent B2 and B3 clades. As recurrent outbreaks and continued virus evolution are expected for EV-D68, a robust real-time PCR assay that detects known strains as well as potential emerging strains is critical for national surveillance and clinical diagnostics. We describe a type-specific EV-D68 real-time RT-PCR (rRT-PCR) assay termed CDC2022, which targets sequences encoding conserved amino acid regions of all extant EV-D68 strains. We targeted three motifs conserved among all strains in the last 60 years. The assay achieved 100% (270/270) sensitivity and 100% (344/344) specificity when tested with a collection of 613 respiratory specimens, compared to the gold-standard EV semi-nested VP1 PCR and sequencing assay (snPCR/Seq). CDC2022 gave negative results with 289/289 non-target viruses, including 104 EV A-D isolates, 165 rhinovirus (RV) isolates or clinical specimens, and 14 other common respiratory viruses. The assay can detect as few as 0.28 CCID50 per reaction. An in silico 'phylo-primer-mismatch' analysis was performed to visualize primer/probe mismatches and to compare CDC2022 with other EV-D68 rRT-PCR assays, including the previous CDC assay (CDC2015) developed in 2014 for clade B1 strains. It showed that CDC2022 has the fewest primer/probe mismatches among all assays analyzed and is suitable for all clades. We additionally tested 11 EV-D68-positive clinical specimens from 2022 that were confirmed by snPCR/Seq, and all were detected. CDC2022 assay could provide a critical tool for molecular surveillance of EV-D68.

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Section: Introductionmentioning

confidence: 99%

Type-specific EV-D68 real-time RT-PCR assay for the detection of all extant enterovirus D68 strains

Ng¹,

Nix²,

Rogers³

et al. 2022

Preprint

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“…To minimize ATP mimicking compounds, we avoided analogs with R-groups at positions equivalent to the N 6 and the N 9 position of the ATP molecule (orange circle and red circle respectively) (Figure 4 A). Instead, R-groups at the N 8 position (green circle) and the 2-position were selected in the analogs to optimize binding to the 2C pocket. To explore this pharmacophore (Figure 4 B), we performed a geometric-based similarity study using binary fingerprints and selected 45 analogs from an in-house library, and tested them in the cell-based CPE inhibition assay against EV-A71 using Vero cells.…”

Section: Resultsmentioning

confidence: 99%

“…A) Comparison of the chemical structures of adenosine triphosphate (ATP), SJW-2C-14, and SJW-2C-69 showing that by including R-groups at the N 8 position (green circle) and by avoiding R-groups at the N 6 (orange circle) and N 9 (red circle) positions, we could select analogs that were different from ATP. B) Pharmacophore model developed to select analogs from the in-house library.…”

Section: Resultsmentioning

confidence: 99%

“…In a relatively small number of infections, EV-A71 can lead to more serious complications such as meningitis, encephalitis, and acute flaccid myelitis 3 and in the Asia-Pacific region, EV-A71 outbreaks have had an overall mortality rate of 0.5 to 19 % 4 . The picornavirus EV-D68 is responsible for acute flaccid myelitis outbreaks in multiple countries, including the USA [5][6][7][8] , where there have been 682 confirmed cases since 2014 9 . Poliovirus (PV) causes paralytic poliomyelitis and although almost eradicated, it still poses a threat due to the reversion of attenuated vaccines to pathogenic vaccine-derived PV 10,11 , with cases recently reported in London and New York state.…”

Section: Introductionmentioning

confidence: 99%

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Development of Enterovirus anti-viral agents that target the viral 2C protein

Kejriwal¹,

Evans²,

Calabrese³

et al. 2022

Preprint

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The enterovirus (EV) genus includes a number of important human and animal pathogens. EV-A71, EV-D68, poliovirus (PV), and coxsackievirus (CV) outbreaks have affected millions worldwide causing a range of upper respiratory, skin, neuromuscular diseases, including acute flaccid myelitis, and hand-foot-and-mouth disease. There are no FDA-approved anti-viral therapeutics for these enteroviruses. In this study, we describe novel broad spectrum anti-viral compounds targeting the conserved non-structural viral protein 2C that have low micro-molar to nanomolar IC50 values. The selection of resistant mutants resulted in amino acid substitutions in the viral capsid protein, implying a role for 2C in capsid assembly, as has been seen in PV. The assembly and encapsidation stages of the viral life cycle are not fully understood and the inhibitors reported here could be useful probes in understanding these processes.

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“…Thus, far there has only been one case of EV-D68 being found in the spinal tissue of a patient diagnosed with AFM. This was in a 5-year-old patient diagnosed in 2008 where authors found EV-D68 RNA and protein in post-mortem autopsy in his anterior horn motor units ( 33 ). This further supports the hypothesis that EV-D68 plays a role in the pathobiology of AFM.…”

Section: Etiologymentioning

confidence: 97%

Acute flaccid myelitis a review of the literature

Dinov

Donowitz

2022

Front. Neurol.

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Acute flaccid myelitis (AFM) is a rare neurological disorder that first rose to national attention in 2014. This neurological disorder has a biennial presentation with every other even year being a peak year. Most patients present in childhood 5 days after a prodromal infection. Patients usually present with muscle weakness and hypo or areflexia in the summer or fall months. Clinical outcomes are variable however most patients do not improve. Currently there are no definitive prognostic factors or etiologies found. However, it is thought that enterovirus-D68 (EV-D68) could be a potential component in the pathobiology of AFM. Treatment options are limited with variable options and no consensus. Supportive therapy has been shown to be the most effective thus far. With our review of the literature, we highlight the recent growing evidence of a possible relationship between EV-D68 and AFM. Additionally, we identify the knowledge gaps in AFM with treatment and prognostic factors.

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Enterovirus D68 in the Anterior Horn Cells of a Child with Acute Flaccid Myelitis

Cited by 28 publications

References 6 publications

Type-specific EV-D68 real-time RT-PCR assay for the detection of all extant enterovirus D68 strains

Type-specific EV-D68 real-time RT-PCR assay for the detection of all extant enterovirus D68 strains

Development of Enterovirus anti-viral agents that target the viral 2C protein

Acute flaccid myelitis a review of the literature

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