The #neonatal Fc #receptor is a pan- #echovirus receptor (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

The neonatal Fc receptor is a pan-echovirus receptor

Stefanie Morosky, Alexandra I. Wells, Kathryn Lemon, Azia S. Evans, Sandra Schamus, Christopher J. Bakkenist, and Carolyn B. Coyne

PNAS published ahead of print February 11, 2019 / DOI: https://doi.org/10.1073/pnas.1817341116

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved January 9, 2019 (received for review October 8, 2018)

 

Significance

Echoviruses are associated with aseptic meningitis and induce severe and sometimes fatal disease in neonates and young infants. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. FcRn is expressed on the surface of the human placenta, and throughout life on intestinal enterocytes, liver hepatocytes, and in the microvascular endothelial cells that line the blood–brain barrier. This pattern of expression is consistent with the organ sites targeted by echoviruses in humans, as the primary entry site of infection is the intestinal and secondary sites of infection include the liver and brain. These findings provide important insights into echovirus pathogenesis and may explain the enhanced susceptibility of neonates to echovirus-induced disease.

 

Abstract

Echoviruses are amongst the most common causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease, including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglobulin (β2M) renders cells resistant to infection by a panel of echoviruses at the stage of virus attachment, and that a blocking antibody to β2M inhibits echovirus infection in cell lines and in primary human intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders nonpermissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echovirus particles and neutralizes infection. Lastly, we show that neonatal mice expressing human FcRn are more susceptible to echovirus infection by the enteral route. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.

echovirus – neonatal Fc receptor – enterovirus – virus receptor – FcRn

 

Footnotes

1 S.M. and A.I.W. contributed equally to this work.

2 To whom correspondence should be addressed. Email: coynec2@pitt.edu.

Author contributions: A.I.W., K.L., C.J.B., and C.B.C. designed research; S.M., A.I.W., K.L., A.S.E., S.S., C.J.B., and C.B.C. performed research; S.M., A.I.W., K.L., A.S.E., S.S., C.J.B., and C.B.C. analyzed data; and S.M., A.I.W., A.S.E., C.J.B., and C.B.C. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1817341116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Enterovirus; Echovirus; Pediatrics.

——

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#Evidence for #cross- #protection to subsequent febrile #respiratory illness episodes from prior #infections by different viruses among #Singapore military #recruits 2009-2014 (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Evidence for cross-protection to subsequent febrile respiratory illness episodes from prior infections by different viruses among Singapore military recruits 2009-2014

I-Cheng Mark, Chen Jin, Phang Loh, Cheryl X P Chuah, Qiu Han Christine Gao, Yinxiaohe Sun, Sock Hoon Ng, Wee-Hong Victor Koh, Ee Hui Goh, Xiahong Zhao, Paul Anantharajah Tambyah, Alex R Cook, Jeremiah Chng, Junxiong Pang, Boon-Huan Tan, Vernon J Lee

The Journal of Infectious Diseases, jiz046, https://doi.org/10.1093/infdis/jiz046

Published: 05 February 2019

 

Abstract

Background

Few studies have studied relative cross-protection between different groups of viruses through studies of sequential infections in humans. We aimed to investigate presence of short-lived relative cross-protection between specific prior viral infections and subsequent febrile respiratory illness (FRI).

Methods

Basic Military Training (BMT) intakes between December 2009 and December 2014 were recruited, with the first FRI as the entry point. ResPlex II assays and real-time PCR assays were used to detect viral pathogens in the samples collected, followed by survival analyses to determine if infection with particular viruses conferred short-lived relative cross-protection against FRI.

Results

Prior infection by adenovirus (Hazard ratio (HR) 0.24, 95% confidence intervals (CI) 0.14 – 0.44) or influenza virus infections (HR 0.52, 95% CI 0.38 – 0.73) conferred relative protection against subsequent FRI. Results were statistically significant at p<0.001 even after adjusting for the FRI experience by time from enlistment. Adenovirus-positive FRI episodes tended to confer protection against subsequent infection by adenovirus, coronavirus, entero/rhinovirus and influenza virus infections (p-values from 0.062 to 0.093), while influenza-positive FRI episodes tended confer protection against adenovirus (p=0.044) and influenza virus infections (p=0.081).

Conclusion

Prior adenovirus and influenza virus infections conferred cross-protective effects to subsequent FRI episodes relative to other circulating viruses.

Antibodies, Cell-mediated immunity, Vaccine, Cohort studies, Surveillance, Cross-Protection, Serology

Issue Section:Major Article

This content is only available as a PDF.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Keywords: Seasonal Influenza; Adenovirus; Enterovirus.

——

Validating #Enterovirus D68-2Apro as an #Antiviral Drug #Target and the Discovery of #Telaprevir as a Potent D68-2Apro Inhibitor (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Validating Enterovirus D68-2Apro as an Antiviral Drug Target and the Discovery of Telaprevir as a Potent D68-2Apro Inhibitor

Rami Musharrafieh, Chunlong Ma, Jiantao Zhang, Yanmei Hu, Jessica M. Diesing, Michael T. Marty, Jun Wang

DOI: 10.1128/JVI.02221-18

 

ABSTRACT

Enterovirus D68 (EV-D68) is a viral pathogen that leads to severe respiratory illness and has been linked with the development of acute flaccid myelitis (AFM) in children. No vaccines or antivirals are currently available for EV-D68 infection, and treatment options for hospitalized patients are limited to supportive care. Here, we report the expression of the EV-D68 2A protease (2Apro) and characterization of its enzymatic activity. Furthermore, we discovered telaprevir, an FDA-approved drug used for the treatment of Hepatitis C virus infections, as a potent antiviral against EV-D68 by targeting the 2Apro enzyme. Using FRET-based substrate cleavage assay, we showed that the purified EV-D68 2Apro has proteolytic activity selective against a peptide sequence corresponding to the viral VP1-2A polyprotein junction. Telaprevir inhibits EV-D68 2Apro through a nearly irreversible, biphasic binding mechanism. In cell culture, telaprevir showed submicromolar to low micromolar potency against several recently circulating neurotropic strains of EV-D68 in different human cell lines. To further confirm the antiviral drug target, serial viral passage experiments were performed to select for resistance against telaprevir. An N84T mutation near the active site of 2Apro was identified in resistant viruses, and this mutation reduced the potency of telaprevir in both the enzymatic and cellular antiviral assays. Collectively, we report for the first time the in vitro enzymatic activity of EV-D68 2Aproand the identification of telaprevir as a potent EV-D68 2Apro inhibitor. These findings implicate EV-D68 2Apro as an antiviral drug target and highlight the repurposing potential of telaprevir to treat EV-D68 infection.

 

IMPORTANCE:

A 2014 EV-D68 outbreak in the United States has been linked to the development of acute flaccid myelitis in children. Unfortunately, no treatment options against EV-D68 are currently available, and the development of effective therapeutics is urgently needed. Here, we characterize and validate a new EV-D68 drug target, the 2Apro, and identify telaprevir—an FDA approved drug used to treat hepatitis C virus (HCV) infections—as a potent antiviral with a novel mechanism towards 2Apro. 2Apro functions as a viral protease that cleaves a peptide sequence corresponding to the VP1-2A polyprotein junction. Binding of telaprevir potently inhibits its enzymatic activity, and using drug resistance selection, we show that the potent antiviral activity of telaprevir was due to 2Apro inhibition. This is the first inhibitor to selectively target the 2Apro from EV-D68 and can be used as a starting point for the development of selective EV-D68 therapeutics.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antivirals; Enterovirus; EV-D68; Telaprevir.

——

#Genomic Analyses of #AFM Cases among a #Cluster in #Arizona Provide Further #Evidence of #EVD68 Role (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

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, Kathryn Fitzpatrick,Gholamabbas Amin Ostovar, Eric Alsop, Elizabeth Hutchins, Kendall Jensen, Paul Keim, David M. Engelthaler

Peter Palese, Editor

DOI: 10.1128/mBio.02262-18

 

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: Enterovirus; EV-D68; USA; Arizona; Acute flaccid myelitis.

—–

Emergence of #EVD68 clade D1, #France, August to November 2018 (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Emergence of enterovirus D68 clade D1, France, August to November 2018

Antonin Bal1,2,3,4, Marina Sabatier1,2,3, Thierry Wirth5,6, Marianne Coste-Burel7, Mouna Lazrek8, Karl Stefic9,10, Karen Brengel-Pesce4, Florence Morfin2,3, Bruno Lina1,2,3, Isabelle Schuffenecker1,2, Laurence Josset1,2,3

Affiliations: 1 Centre National de Référence des Enterovirus et Parechovirus, Hospices Civils de Lyon, Lyon, France; 2 Laboratoire de Virologie, Institut des Agents Infectieux, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France; 3 Université Lyon 1, Faculté de Médecine Lyon Est, CIRI, Inserm U1111, CNRS UMR5308, Virpath, Lyon, France; 4 Laboratoire Commun de Recherche Hospices Civils de Lyon-bioMerieux, Centre Hospitalier Lyon Sud, Pierre-Bénite, France; 5 Laboratoire Biologie Intégrative des Populations, Evolution Moléculaire, EPHE, PSL Université, Paris, France; 6 Institut Systématique, Evolution, Biodiversité (ISYEB), EPHE, MNHN, CNRS, Sorbonne Université, Paris, France; 7 Laboratoire de Virologie, UIC9 CIC infectieux, Centre Hospitalier Universitaire de Nantes, Nantes, France; 8 Laboratoire de Virologie, EA3610, Centre Hospitalier Universitaire de Lille, Université de Lille, Lille, France; 9 INSERM U1259, Université de Tours, Tours, France; 10 Laboratoire de Virologie and CNR VIH-Laboratoire Associé, Centre Hospitalier Régional Universitaire de Tours, Tours, France

Correspondence: Laurence Jossetlaurence.jossetchu-lyon.fr

Citation style for this article: Bal Antonin, Sabatier Marina, Wirth Thierry, Coste-Burel Marianne, Lazrek Mouna, Stefic Karl, Brengel-Pesce Karen, Morfin Florence, Lina Bruno, Schuffenecker Isabelle, Josset Laurence. Emergence of enterovirus D68 clade D1, France, August to November 2018. Euro Surveill. 2019;24(3):pii=1800699. https://doi.org/10.2807/1560-7917.ES.2019.24.3.1800699

Received: 26 Dec 2018;   Accepted: 16 Jan 2019

 

Abstract

We report a seasonal increase of enterovirus D68 (EV-D68) cases in France, with 54 cases detected between 19 August and 14 November 2018. Molecular typing revealed that 20 of 32 of the isolates belonged to clade D1, only sporadically detected before in France. Median age of D1-cases was 42 years, 10 developed severe respiratory signs and one had neurological complications. The 2018-D1 viruses showed a genetic divergence of 3.34 % with D1 viruses identified previously.

©  This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: Enterovirus; EV-D68; France.

——

High permissiveness for #genetic exchanges between #enteroviruses of species A, including enterovirus 71, favours #evolution through intertypic #recombination in #Madagascar (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

High permissiveness for genetic exchanges between enteroviruses of species A, including enterovirus 71, favours evolution through intertypic recombination in Madagascar

Romain Volle, Richter Razafindratsimandresy, Marie-Line Joffret, Maël Bessaud, Sendraharimanana Rabemanantsoa, Seta Andriamamonjy, Jonhson Raharinantoanina, Bruno Blondel,Jean-Michel Heraud, Jean-Luc Bailly, Francis Delpeyroux

DOI: 10.1128/JVI.01667-18

 

ABSTRACT

Human enteroviruses of species A (EV-A) are the leading cause of hand-foot-and-mouth disease (HFMD). EV-A71 is frequently implicated in HFMD outbreaks and can also cause severe neurological manifestations. We investigated the molecular epidemiological processes at work and the contribution of genetic recombination to the evolutionary history of EV-A in Madagascar, focusing on the recently described EV-A71 genogroup F in particular. Twenty-three EV-A isolates, mostly collected in 2011 from healthy children living in various districts of Madagascar, were characterised by whole-genome sequencing. Eight different types were identified, highlighting the local circulation and diversity of EV-A. Comparative genome analysis revealed evidence of frequent recent intra- and intertypic genetic exchanges between the non-capsid sequences of Madagascan EV-A isolates. The three EV-A71 isolates had different evolutionary histories in terms of recombination, with one isolate displaying a mosaic genome resulting from recent genetic exchanges with Madagascan coxsackieviruses A7 and possibly -A5 and -A10 or common ancestors. The engineering and characterisation of recombinants generated from progenitors belonging to different EV-A types or EV-A71 genogroups with distantly related non-structural sequences indicated a high level of permissiveness for intertypic genetic exchange in EV-A. This permissiveness suggests that the primary viral functions associated with the non-structural sequences have been highly conserved, through the diversification and evolution of the EV-A species. No outbreak of disease due to EV-A has yet been reported in Madagascar, but the diversity, circulation and evolution of these viruses justify surveillance of EV-A circulation and HFMD cases, to prevent possible outbreaks due to emerging strains.

 

IMPORTANCE

Human enteroviruses of species A (EV-A), including EV-A71, are the leading cause of hand-foot-and-mouth disease (HFMD), and may also cause severe neurological manifestations. We investigated the circulation and molecular evolution of EV-A in Madagascar, focusing particularly on the recently described EV-A71 genogroup F. Eight different types, mostly collected in 2011, were identified, highlighting the local circulation and diversity of EV-A. Comparative genome analysis revealed evidence of frequent genetic exchanges between the different types of isolates. The three EV-A71 isolates had different evolutionary histories in terms of recombination. The engineering and characterisation of recombinants involving progenitors belonging to different EV-A types indicated a high degree of permissiveness for genetic exchange in EV-A. No outbreak of disease due to EV-A has yet been reported in Madagascar, but the diversity, circulation and evolution of these viruses justify the surveillance of EV-A circulation, to prevent possible HFMD outbreaks due to emerging strains.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Enterovirus; Recombination; EV-A71; Coxsackievirus A5-A7-A10; HFMD; Madagascar.

——

Acute Flaccid #Myelitis Associated with #Enterovirus D68 in #Children, #Argentina, 2016 (Emerg Infect Dis., edited)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Edited.]

Volume 25, Number 3—March 2019 / Dispatch

Acute Flaccid Myelitis Associated with Enterovirus D68 in Children, Argentina, 2016

Carolina M. Carballo  , Marcela García Erro, Nora Sordelli, Gabriel Vazquez, Alicia S. Mistchenko, Claudia Cejas, Manlio Rodriguez, Daniel M. Cisterna, Maria Ceclilia Freire, Maria M. Contrini, and Eduardo L. Lopez

Author affiliations: de Niños “Ricardo Gutiérrez,” Buenos Aires, Argentina (C.M. Carballo, M. García Erro, N. Sordelli, A.S. Mistchenko, M. Rodriguez, M.M. Contrini, E.L. Lopez); Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) Hospital, Buenos Aires (G. Vazquez, C. Cejas); Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) “Dr. Carlos G. Malbrán,” Buenos Aires (D.M. Cisterna, M.C. Freire)

 

Abstract

After a 2014 outbreak of severe respiratory illness caused by enterovirus D68 in the United States, sporadic cases of acute flaccid myelitis have been reported worldwide. We describe a cluster of acute flaccid myelitis cases in Argentina in 2016, adding data to the evidence of association between enterovirus D68 and this polio-like illness.

____

We report a cluster of acute flaccid myelitis (AFM) cases in Buenos Aires, Argentina, in 2016. AFM was defined as acute flaccid paralysis (AFP) with magnetic resonance imaging (MRI) showing lesions predominantly affecting the gray matter of the spinal cord (1). We prospectively studied all patients with AFP who were admitted to Hospital de Niños “Ricardo Gutiérrez” in Buenos Aires during April 24–August 24, 2016 under the Argentine National Surveillance Acute Flaccid Paralysis Program for poliovirus as part of the World Health Organization AFP Program in the Americas. We obtained fecal samples or rectal swab specimens, serum samples, nasopharyngeal swab specimens, and cerebrospinal fluid (CSF) samples.

Fecal samples were tested at the National Reference Center for the Argentine National Surveillance Acute Flaccid Paralysis Program for enterovirus, including wild-type and vaccine-derived poliovirus. We screened clinical samples for enterovirus D68 (EV-D68) using a panrhinovirus and enterovirus nested PCR of enterovirus targeting the 5′ untranslated region (2). We purified the amplified products and prepared them for Sanger sequencing. We performed BLAST searches (https://blast.ncbi.nlm.nih.gov/Blast.cgi) of GenBank sequences to identify which picornavirus was present. We obtained viral protein 1 partial sequences as previously described (3). In addition, we studied a wide panel of viruses (parainfluenza virus 1, 2, and 3; influenza A/B; respiratory syncytial virus; adenovirus; metapneumovirus; rhinovirus; varicella zoster virus; herpes simplex virus; cytomegalovirus) by reverse transcription PCR (RT-PCR) and studied bacteria by culture. We performed MRI and electromyography for all patients.

Fourteen children were admitted with AFP during April–August 2016. Six were confirmed to have AFM by case definition; the other 8 had alternative diagnoses, including Guillain-Barré syndrome (3), influenza virus myositis (2), encephalitis by echovirus (in 1 child with Down syndrome), acute transient hip synovitis (1), and transverse myelitis (1). Patients’ clinical, demographic, and outcome findings are shown in Table 1, diagnostic findings in Table 2.

In 4 (66.7%) of 6 patients, we confirmed EV-D68 infection by nested RT-PCR. In 1 patient, enterovirus was detected but not typed; in 1 patient, no agent was detected. All patients had distinctive neuroimaging changes. We followed confirmed AFM cases for 6 months to assess clinical improvement.

The median age of patients with AFM was 3.9 (range 1–5) years; 4 (66.7%) of the 6 were female, and 3 (50%) had a history of asthma. All patients had prodromal signs or symptoms before onset of neurologic symptoms: 100% had upper respiratory tract infection (URTI); 4 (66.7%) had fever: and 1 (16.7%) had vomiting and abdominal pain. Neurologic symptoms appeared 1–11 (median 2) days after URTI symptoms.

Results of hematology and chemistry analysis were normal for 5 (83%) patients. Patient 1 had leukocytosis (leukocytes 18,000 cells/mm3, with 82% neutrophils) and elevated levels of alanine aminotransferase (103 IU/L [reference 10–43 IU/L]), aspartate aminotransferase (97 IU/L [reference 10–35 IU/L]), and creatine kinase (6,591 IU/L [reference 24–170 IU/L]). During follow-up, patient 1 showed an increased creatine kinase level that could not be related to enterovirus infection.

All confirmed AFM case-patients showed T2 gray matter hyperintensity within the spinal cord on MRI. Electromyography showed early signs of denervation and low motor neuron function in all 5 patients in whom the test could be done. Specimen collection was performed 9.5 (range 3–30) days after URTI symptoms started and 7.5 (range 1–18) days after onset of neurologic symptoms.

Results of nested RT-PCR for enterovirus were negative for all CSF samples; results of the respiratory virus panel were negative for all patients. Neither bacteria nor fungus were isolated in blood or CSF samples. Serum PCR to identify herpes simplex virus, varicella zoster virus, and cytomegalovirus also yielded negative results.

Intravenous immunoglobulin was empirically infused in 5 (83%) patients; 2 (33%) received systemic corticosteroids. Three patients required intensive care unit admission. All patients had neurologic sequelae: persisting palsy in >1 limbs and atrophy of muscles with a shortening of limbs. Two patients required chronic noninvasive ventilatory support during 6 months of follow-up. No patients died.

 

Conclusions

AFM has been associated with different etiologic agents (1). EV-D68 is a nonpolio enterovirus characterized by affinity for α2–6-linked sialic acids typically found in the upper respiratory tract, making the respiratory tract the preferred target for EV-D68 replication, unlike most enteroviruses, which replicate in the gut (1,7). Although there is no definitive evidence of causality between EV-D68 and AFM, since the 2014 EV-D68 respiratory outbreak in North America, AFM cases possibly associated with EV-D68 have been reported in the United States, Canada, Australia, Norway, Great Britain, and France (1,4). We report a cluster of AFM associated with EV-D68 in Argentina; another institution in Argentina (Hospital Garrahan) has also reported a case series of AFM (5,6).

The cluster in this report occurred over a 3-month period, during the 2016 autumn–winter season, which is the typical enterovirus season in Buenos Aires. Clinical and neurologic findings were similar to those of cases reported in other countries, including URTI preceding the neurologic features (4,8,9). Patients were admitted with asymmetric, acute, and progressive weakness of limbs; areflexia; and muscle pain. These symptoms have been reported as polio-like syndrome; however, testing and MRI should be performed for multiple viruses, including enteroviruses and EV-D68, to detect distinctive spinal cord lesions. No sensory sensitivity involvement was observed. Two patients had cranial nerve dysfunction. Laboratory findings were similar to those previously described, including CSF abnormalities (1,4,8).

Different hypotheses to explain difficulties in isolation of EV-D68 have been reported (4). It is possible that most of the nasopharyngeal specimens in previous studies and in our cluster were taken after 7 days of URTI, when the viral load is usually low, as reported by Imamura et al. (10). In our case series, enterovirus was identified in respiratory secretions in 5 (83.3%) of 6 patients, even though specimen collection was performed >7 days (mean 9 days) after AFM onset (in 1 patient, viral load was too low for genotyping). The negative nasopharyngeal specimen was collected at 18 days after onset.

Isolation of EV-D68 in fecal samples is uncommon because the virus is both heat and acid labile (1). However, in 2 (33.3%) of our 6 patients, EV-D68 was identified in fecal samples.

Reported rates of CSF detection of known neurotropic enteroviruses, such as polioviruses and enterovirus A71, are as low as 0%–5%, although viruses could be detected in brain or spinal cord tissue (4,11). A recent mouse model of AFM caused by EV-D68 showed that EV-D68 infects anterior horn motor neurons, resulting in motor neuron death (9). In our series, CSF samples tested negative for EV-D68 and other pathogens.

No specific treatment for EV-D68 AFM is available; the US Centers for Disease Control and Prevention recommends only support measures (7,12). Zhang et al. demonstrated that commercial immunoglobulin contained high levels of neutralizing antibodies against EV-D68 strains during the 2014 outbreak in the United States (13). No vaccines are available.

EV-D68 belonging to subclade B3 was identified in our cluster by molecular sequencing. This subclade was associated with EV-D68 circulation in the United States and Europe in 2016 (14).

We show a cluster of AFM associated with EV-D68 in Argentina. Our findings contribute to global evidence of EV-D68 as a possible cause of localized polio-like illness.

___

Dr. Carballo is a pediatric infectious diseases specialist at the Hospital de Niños “Ricardo Gutierrez” in Buenos Aires. Her research interests are pediatric infectious diseases.

 

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Suggested citation for this article: Carballo CM, García Erro M, Sordelli N, Vazquez G, Mistchenko AS, Cejas C, et al. Acute flaccid myelitis associated with enterovirus D68 in children, Argentina, 2016. Emerg Infect Dis. 2019 Mar [date cited]. https://doi.org/10.3201/eid2503.170897

DOI: 10.3201/eid2503.170897

Original Publication Date: 1/2/2019

Keywords: AFP; AFM; EV-D68; Argentina.

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