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Messali S, Bertelli A, Dotta L, Giovanetti M, Sclavi L, Venneri G, Ciccozzi M, Badolato R, Caruso A, Caccuri F. Outbreak of Enterovirus D68 in Young Children, Brescia, Italy, August to November 2024. J Med Virol 2025; 97:e70372. [PMID: 40297997 PMCID: PMC12038777 DOI: 10.1002/jmv.70372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 04/15/2025] [Accepted: 04/18/2025] [Indexed: 04/30/2025]
Abstract
Enterovirus D68 (EV-D68) is responsible for a plethora of clinical manifestations ranging from asymptomatic infections to severe respiratory symptoms and neurological disorders. EV-D68 was first detected in children with pneumonia in 1962 and, from then, only sporadic cases were reported until 2014, when outbreaks were notified across the world. After the withdrawal of preventive measures against SARS-CoV-2, a significant increase in EV-D68 infections has been reported in 2021-2022. A surveillance program to evaluate the incidence of enterovirus/rhinovirus (EV/RV) infections was implemented at the Brescia Civic Hospital, Italy. Fifty-five EV/RV-positive respiratory samples, belonging to pediatric patients, were subjected to NGS. We observed that 61.8% of samples were positive for EV, with EV-D68 as the most prevalent genotype predominantly detected between August and November 2024. Phylogenetic analysis revealed that EV-D68 sequences formed two monophyletic clades corresponding to the A2 and B3 lineages, highlighting their recent introduction in Italy. Interestingly, 40% of pediatric EV-D68 infections were detected with at least one other EV/RV. Our study highlights the crucial role played by genomic surveillance of respiratory infections to monitor the circulation of emerging and re-emerging viruses, as well as their evolution. This will be fundamental to enable prompt intervention strategies.
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Affiliation(s)
- Serena Messali
- Section of Microbiology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
- Institute of MicrobiologyASST‐Spedali Civili, BresciaBresciaItaly
| | - Anna Bertelli
- Institute of MicrobiologyASST‐Spedali Civili, BresciaBresciaItaly
| | - Laura Dotta
- Department of Clinical and Experimental Sciences, Pediatric Clinic and Institute for Molecular Medicine “A. Nocivelli”University of Brescia and ASST‐Spedali Civili di BresciaBresciaItaly
| | - Marta Giovanetti
- Sciences and Technologies for Sustainable Development and One HealthUniversity of Campus Bio‐MedicoRomeItaly
- Instituto René RachouFundação Oswaldo CruzBelo HorizonteMinas GeraisBrazil
| | - Leonardo Sclavi
- Section of Microbiology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
| | - Giulia Venneri
- Section of Microbiology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
| | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular EpidemiologyUniversity of Campus Bio‐MedicoRomeItaly
| | - Raffaele Badolato
- Department of Clinical and Experimental Sciences, Pediatric Clinic and Institute for Molecular Medicine “A. Nocivelli”University of Brescia and ASST‐Spedali Civili di BresciaBresciaItaly
| | - Arnaldo Caruso
- Section of Microbiology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
- Institute of MicrobiologyASST‐Spedali Civili, BresciaBresciaItaly
| | - Francesca Caccuri
- Section of Microbiology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
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Cox SN, Casto AM, Franko NM, Chow EJ, Han PD, Gamboa L, Pfau B, Xie H, Kong K, Sereewit J, Rolfes MA, Mosites E, Uyeki TM, Greninger AL, Carone M, Shim MM, Bedford T, Shendure J, Boeckh M, Englund JA, Starita LM, Roychoudhury P, Chu HY. Clinical and Genomic Epidemiology of Coxsackievirus A21 and Enterovirus D68 in Homeless Shelters, King County, Washington, USA, 2019-2021. Emerg Infect Dis 2024; 30:2250-2260. [PMID: 39447143 PMCID: PMC11521184 DOI: 10.3201/eid3011.240687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024] Open
Abstract
Congregate homeless shelters are disproportionately affected by infectious disease outbreaks. We describe enterovirus epidemiology across 23 adult and family shelters in King County, Washington, USA, during October 2019-May 2021, by using repeated cross-sectional respiratory illness and environmental surveillance and viral genome sequencing. Among 3,281 participants >3 months of age, we identified coxsackievirus A21 (CVA21) in 39 adult residents (3.0% [95% CI 1.9%-4.8%] detection) across 7 shelters during October 2019-February 2020. We identified enterovirus D68 (EV-D68) in 5 adult residents in 2 shelters during October-November 2019. Of 812 environmental samples, 1 was EV-D68-positive and 5 were CVA21-positive. Other enteroviruses detected among residents, but not in environmental samples, included coxsackievirus A6/A4 in 3 children. No enteroviruses were detected during April 2020-May 2021. Phylogenetically clustered CVA21 and EV-D68 cases occurred in some shelters. Some shelters also hosted multiple CVA21 lineages.
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Yasaie S, Mousavi Nasab SD, Shams S, Ferdousi A, Kaghazian H. Evaluation of the detection of diarrhoea-associated RNA viruses in immunocompromised children in Iran. Infect Prev Pract 2024; 6:100370. [PMID: 38855735 PMCID: PMC11153253 DOI: 10.1016/j.infpip.2024.100370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 03/28/2024] [Indexed: 06/11/2024] Open
Abstract
Background Gastroenteritis accounts for about 10% of the deaths among children, especially in immunocompromised children. Few studies on the prevalence of gastrointestinal infections caused by RNA viruses have been done in Iran. The aim of the study was to evaluate the detection of RNA viruses causing diarrhoea using a multiplex PCR. Methods Stool samples were collected from 130 paediatric patients with diarrhoea who had acute lymphocytic leukaemia, non-Hodgkin lymphoma, and retinoblastoma. After RNA extraction and synthesis of cDNA, multiplex PCR was done to evaluate the presence of rotavirus, norovirus, astrovirus, and enterovirus. Results There were 9 (6.9%), 7 (5.4%), 3 (2.3%), and 6 (4.6%) cases of rotavirus, norovirus, astrovirus, and enterovirus detected, respectively. One case of co-infection with astrovirus and norovirus was observed. Conclusions This is the first report from Iran which identified the presence of common RNA viruses causing diarrhoea in immunocompromised children. Increased awareness of these viruses will enable healthcare professionals to improve strategies and policies to control spread and infection caused by these viruses.
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Affiliation(s)
- Shokouh Yasaie
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
| | - Seyed Dawood Mousavi Nasab
- Department of Arboviruses and Viral Hemorrhagic Fevers (National Reference Laboratory), Pasteur Institute of Iran, Tehran, Iran
| | - Saeed Shams
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Atousa Ferdousi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
| | - Hooman Kaghazian
- Department of Research and Development, Production and Research Complex, Pasteur Institute of Iran, Tehran, Iran
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4
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Rueca M, Vairo F, Spaziante M, Fabeni L, Forbici F, Berno G, Gruber CEM, Picone S, Ajassa C, Girardi E, Maggi F, Valli MB. Molecular Genotyping of Circulating Enterovirus in the Lazio Region from 2012 to 2023. Viruses 2024; 16:1013. [PMID: 39066176 PMCID: PMC11281471 DOI: 10.3390/v16071013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/31/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
Enteroviruses (EVs) are ubiquitous viruses that circulate worldwide, causing sporadic or epidemic infections, typically during the summer and fall. They cause a broad spectrum of illnesses, ranging from an unspecified febrile clinical presentation to a severe illness. EVs are recognized to be the most frequent etiological agents of aseptic meningitis in children. However, as the infection is usually mild and self-limiting, it remains underestimated, and the epidemiology of EVs is poorly understood. To date, no vaccine or effective therapy for all types of enteroviruses is available, and EVs constitute a public health concern. Here, we investigated the molecular epidemiology of EV strains circulating in the Lazio region over a 10-year time span (2012-2023) by using a sequence-typing approach and phylogenetic analysis. The epidemiological trend of EV infection has undergone changes during the SARS-CoV-2 pandemic (2020-2021), which resulted in a modification in terms of the number of diagnosed cases and seasonality. From 2022, the circulation of EVs showed a behavior typical of the pre-pandemic period, although changes in predominantly circulating strains have been noted. Both epidemic and sporadic circulation events have been characterized in the Lazio region. Further analyses are needed to better characterize any strain with higher potential pathogenic power and to identify possible recombinant strains.
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Affiliation(s)
- Martina Rueca
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (M.R.); (F.F.); (G.B.); (C.E.M.G.); (F.M.); (M.B.V.)
| | - Francesco Vairo
- Regional Service for Surveillance and Control of Infectious Diseases (SERESMI)-Lazio Region, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (F.V.); (M.S.)
| | - Martina Spaziante
- Regional Service for Surveillance and Control of Infectious Diseases (SERESMI)-Lazio Region, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (F.V.); (M.S.)
| | - Lavinia Fabeni
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (M.R.); (F.F.); (G.B.); (C.E.M.G.); (F.M.); (M.B.V.)
| | - Federica Forbici
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (M.R.); (F.F.); (G.B.); (C.E.M.G.); (F.M.); (M.B.V.)
| | - Giulia Berno
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (M.R.); (F.F.); (G.B.); (C.E.M.G.); (F.M.); (M.B.V.)
| | - Cesare Ernesto Maria Gruber
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (M.R.); (F.F.); (G.B.); (C.E.M.G.); (F.M.); (M.B.V.)
| | - Simonetta Picone
- Neonatology and Neonatal Intensive Care Unit, Policlinico Casilino, 00169 Rome, Italy;
| | - Camilla Ajassa
- Department of Public Health and Infectious Diseases, Sapienza University Hospital “Policlinico Umberto I”, 00161 Rome, Italy;
| | - Enrico Girardi
- Scientific Direction, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy;
| | - Fabrizio Maggi
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (M.R.); (F.F.); (G.B.); (C.E.M.G.); (F.M.); (M.B.V.)
| | - Maria Beatrice Valli
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (M.R.); (F.F.); (G.B.); (C.E.M.G.); (F.M.); (M.B.V.)
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Nurmukanova V, Matsvay A, Gordukova M, Shipulin G. Square the Circle: Diversity of Viral Pathogens Causing Neuro-Infectious Diseases. Viruses 2024; 16:787. [PMID: 38793668 PMCID: PMC11126052 DOI: 10.3390/v16050787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/08/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Neuroinfections rank among the top ten leading causes of child mortality globally, even in high-income countries. The crucial determinants for successful treatment lie in the timing and swiftness of diagnosis. Although viruses constitute the majority of infectious neuropathologies, diagnosing and treating viral neuroinfections remains challenging. Despite technological advancements, the etiology of the disease remains undetermined in over half of cases. The identification of the pathogen becomes more difficult when the infection is caused by atypical pathogens or multiple pathogens simultaneously. Furthermore, the modern surge in global passenger traffic has led to an increase in cases of infections caused by pathogens not endemic to local areas. This review aims to systematize and summarize information on neuroinvasive viral pathogens, encompassing their geographic distribution and transmission routes. Emphasis is placed on rare pathogens and cases involving atypical pathogens, aiming to offer a comprehensive and structured catalog of viral agents with neurovirulence potential.
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Affiliation(s)
- Varvara Nurmukanova
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency, 119121 Moscow, Russia
| | - Alina Matsvay
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency, 119121 Moscow, Russia
| | - Maria Gordukova
- G. Speransky Children’s Hospital No. 9, 123317 Moscow, Russia
| | - German Shipulin
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency, 119121 Moscow, Russia
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Grizer CS, Messacar K, Mattapallil JJ. Enterovirus-D68 - A Reemerging Non-Polio Enterovirus that Causes Severe Respiratory and Neurological Disease in Children. FRONTIERS IN VIROLOGY (LAUSANNE, SWITZERLAND) 2024; 4:1328457. [PMID: 39246649 PMCID: PMC11378966 DOI: 10.3389/fviro.2024.1328457] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/10/2024]
Abstract
The past decade has seen the global reemergence and rapid spread of enterovirus D68 (EV-D68), a respiratory pathogen that causes severe respiratory illness and paralysis in children. EV-D68 was first isolated in 1962 from children with pneumonia. Sporadic cases and small outbreaks have been reported since then with a major respiratory disease outbreak in 2014 associated with an increased number of children diagnosed with polio-like paralysis. From 2014-2018, major outbreaks have been reported every other year in a biennial pattern with > 90% of the cases occurring in children under the age of 16. With the outbreak of SARS-CoV-2 and the subsequent COVID-19 pandemic, there was a significant decrease in the prevalence EV-D68 cases along with other respiratory diseases. However, since the relaxation of pandemic social distancing protocols and masking mandates the number of EV-D68 cases have begun to rise again - culminating in another outbreak in 2022. Here we review the virology, pathogenesis, and the immune response to EV-D68, and discuss the epidemiology of EV-D68 infections and the divergence of contemporary strains from historical strains. Finally, we highlight some of the key challenges in the field that remain to be addressed.
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Affiliation(s)
- Cassandra S Grizer
- Department of Microbiology & Immunology, The Henry M. Jackson Foundation for Military Medicine, Uniformed Services University, Bethesda, MD 20814, USA
| | - Kevin Messacar
- The Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Joseph J Mattapallil
- Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA
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7
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Hooi YT, Balasubramaniam VRMT. In vitro and in vivo models for the study of EV-D68 infection. Pathology 2023; 55:907-916. [PMID: 37852802 DOI: 10.1016/j.pathol.2023.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/03/2023] [Accepted: 08/14/2023] [Indexed: 10/20/2023]
Abstract
Enterovirus D68 (EV-D68) is one of hundreds of non-polio enteroviruses that typically cause cold-like respiratory illness. The first EV-D68 outbreak in the United States in 2014 aroused widespread concern among the public and health authorities. The infection was found to be associated with increased surveillance of acute flaccid myelitis, a neurological condition that causes limb paralysis in conjunction with spinal cord inflammation. In vitro studies utilising two-dimensional (2D) and three-dimensional (3D) culture systems have been employed to elucidate the pathogenic mechanism of EV-D68. Various animal models have also been developed to investigate viral tropism and distribution, pathogenesis, and immune responses during EV-D68 infection. EV-D68 infections have primarily been investigated in respiratory, intestinal and neural cell lines/tissues, as well as in small-size immunocompetent rodent models that were limited to a young age. Some studies have implemented strategies to overcome the barriers by using immunodeficient mice or virus adaptation. Although the existing models may not fully recapitulate both respiratory and neurological disease observed in human EV-D68 infection, they have been valuable for studying pathogenesis and evaluating potential vaccine or therapeutic candidates. In this review, we summarise the methodologies and findings from each experimental model and discuss their applications and limitations.
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Affiliation(s)
- Yuan Teng Hooi
- Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia.
| | - Vinod R M T Balasubramaniam
- Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia.
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Singh B, Arora S, Sandhu N. Emerging trends and insights in acute flaccid myelitis: a comprehensive review of neurologic manifestations. Infect Dis (Lond) 2023; 55:653-663. [PMID: 37368373 DOI: 10.1080/23744235.2023.2228407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 06/08/2023] [Accepted: 06/18/2023] [Indexed: 06/28/2023] Open
Abstract
Acute Flaccid Myelitis (AFM) is a neurological condition in the anterior portion of the spinal cord and can be characterised as paraplegia (paralysis of the lower limbs), and cranial nerve dysfunction. These lesions are caused by the infection due to Enterovirus 68 (EV-D68); a member of the Enterovirus (EV) family belongs to the Enterovirus species within the Picornavirus family and a Polio-like virus. In many cases, the facial, axial, bulbar, respiratory, and extraocular muscles were affected, hence reducing the overall quality of the patient's life. Moreover, severe pathological conditions demand hospitalisation and can cause mortality in a few cases. The data from previous case studies and literature suggest that the prevalence is high in paediatric patients, but careful clinical assessment and management can decrease the risk of mortality and paraplegia. Moreover, the clinical and laboratory diagnosis can be performed by Magnetic resonance imaging (MRI) of the spinal cord followed by Reverse transcription polymerase chain reaction (rRT-PCR) and VP1 seminested PCR assay of the cerebrospinal fluid (CSF), stool, and serum samples can reveal the disease condition to an extent. The primary measure to control the outbreak is social distancing as advised by public health administrations, but more effective ways are yet to discover. Nonetheless, vaccines in the form of the whole virus, live attenuated, sub-viral particles, and DNA vaccines can be an excellent choice to treat these conditions. The review discusses a variety of topics, such as epidemiology, pathophysiology, diagnosis/clinical features, hospitalisation/mortality, management/treatment, and potential future developments.
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Affiliation(s)
- Baljinder Singh
- Centre for Pharmaceutical Innovation, University of South Australia, North Terrace, Adelaide, SA, Australia
| | - Sanchit Arora
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India
| | - Navjot Sandhu
- Department of Quality Assurance, ISF College of Pharmacy, Moga, Affiliated to IK Gujral Punjab Technical University, Jalandhar, India
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Acute Flaccid Myelitis: Review of Clinical Features, Diagnosis, and Management with Nerve Transfers. Plast Reconstr Surg 2023; 151:85e-98e. [PMID: 36219869 DOI: 10.1097/prs.0000000000009788] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Acute flaccid myelitis (AFM) is a devastating neurologic condition in children, manifesting as acute limb weakness and/or paralysis. Despite increased awareness of AFM following initiation of U.S. surveillance in 2014, no treatment consensus exists. The purpose of this systematic review was to summarize the most current knowledge regarding AFM epidemiology, cause, clinical features, diagnosis, and supportive and operative management, including nerve transfer. METHODS The authors systematically reviewed the literature based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using multiple databases to search the keywords ("acute flaccid myelitis"), ('acute flaccid myelitis'/exp OR 'acute flaccid myelitis'), and (Acute AND flaccid AND myelitis). Included articles reported on (1) AFM diagnosis and (2) patient-specific data regarding epidemiology, cause, clinical features, diagnostic features, or management of AFM. RESULTS Ninety-nine articles were included in this review. The precise cause and pathophysiologic mechanism of AFM remain undetermined, but AFM is strongly associated with nonpolio enterovirus infections. Clinical presentation typically comprises preceding viral prodrome, pleocytosis, spinal cord lesions on T2-weighted magnetic resonance imaging, and acute onset of flaccid weakness/paralysis with hyporeflexia in at least one extremity. Supportive care includes medical therapy and rehabilitation. Early studies of nerve transfer for AFM have shown favorable outcomes for patients with persistent weakness. CONCLUSIONS Supportive care and physical therapy are the foundation of a multidisciplinary approach to managing AFM. For patients with persistent limb weakness, nerve transfer has shown promise for improving function in distal muscle groups. Surgeons must consider potential spontaneous recovery, patient selection, donor nerve availability, recipient nerve appropriateness, and procedure timing.
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Sooksawasdi Na Ayudhya S, Laksono BM, van Riel D. The pathogenesis and virulence of enterovirus-D68 infection. Virulence 2021; 12:2060-2072. [PMID: 34410208 PMCID: PMC8381846 DOI: 10.1080/21505594.2021.1960106] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In 2014, enterovirus D68 (EV-D68) emerged causing outbreaks of severe respiratory disease in children worldwide. In a subset of patients, EV-D68 infection was associated with the development of central nervous system (CNS) complications, including acute flaccid myelitis (AFM). Since then, the number of reported outbreaks has risen biennially, which emphasizes the need to unravel the systemic pathogenesis in humans. We present here a comprehensive review on the different stages of the pathogenesis of EV-D68 infection – infection in the respiratory tract, systemic dissemination and infection of the CNS – based on observations in humans as well as experimental in vitro and in vivo studies. This review highlights the knowledge gaps on the mechanisms of systemic dissemination, routes of entry into the CNS and mechanisms to induce AFM or other CNS complications, as well as the role of virus and host factors in the pathogenesis of EV-D68.
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Affiliation(s)
| | - Brigitta M Laksono
- Department of Viroscience, Erasmus MC, Dr Molewaterplein 40, GD Rotterdam, The Netherlands
| | - Debby van Riel
- Department of Viroscience, Erasmus MC, Dr Molewaterplein 40, GD Rotterdam, The Netherlands
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11
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Vawter-Lee M, Peariso K, Frey M, Bolikal P, Schaffzin JK, Schwentker A, O'Brien WT, Zamor R, Kerrey BT. Acute Flaccid Myelitis: A Multidisciplinary Protocol to Optimize Diagnosis and Evaluation. J Child Neurol 2021; 36:421-431. [PMID: 33258719 DOI: 10.1177/0883073820975230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Acute flaccid myelitis is an emerging neurologic disease, first described in 2014 and predominantly affecting young children. Acute flaccid myelitis cases tend to spike every 2 years, in the late summer to fall, and the next peak is expected in 2020. The diagnosis of acute flaccid myelitis is often delayed, leading to suboptimal evaluation, including incomplete laboratory assessment. Acute and chronic morbidity are high, and a standardized, multidisciplinary approach to evaluation and treatment is essential to optimizing outcomes. In a review of acute flaccid myelitis patients treated in 2018 at our institution, we noted considerable variability in days to presentation, evaluation, and treatment. In response, the authors developed a protocol for the evaluation and management of pediatric patients suspected of having acute flaccid myelitis. The protocol was developed using local experience/case review, expert consensus, and the relevant literature. The protocol spans the spectrum of care, from initial evaluation in a primary care or emergency setting, to acute hospital management and evaluation and long-term inpatient and rehabilitation settings. The purpose of this report is both to share the findings from our 2018 case review and to disseminate our acute flaccid myelitis protocol. Our hope is that publication of our protocol will both inform the development of a standardized approach to acute flaccid myelitis and to encourage other centers to form a multidisciplinary acute flaccid myelitis team to provide expert care throughout the disease process, from presentation to recovery.
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Affiliation(s)
- Marissa Vawter-Lee
- 2518University of Cincinnati, College of Medicine, Cincinnati, OH, USA.,Division of Neurology, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Katrina Peariso
- 2518University of Cincinnati, College of Medicine, Cincinnati, OH, USA.,Division of Neurology, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Mary Frey
- Division of Emergency Medicine, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Priya Bolikal
- 2518University of Cincinnati, College of Medicine, Cincinnati, OH, USA.,Division of Physical Medicine and Rehabilitation, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Joshua K Schaffzin
- 2518University of Cincinnati, College of Medicine, Cincinnati, OH, USA.,Division of Infectious Diseases, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Ann Schwentker
- 2518University of Cincinnati, College of Medicine, Cincinnati, OH, USA.,Division of Pediatric Plastic and Craniofacial Surgery, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - William T O'Brien
- 2518University of Cincinnati, College of Medicine, Cincinnati, OH, USA.,Division of Neuroradiology, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Ronine Zamor
- 2518University of Cincinnati, College of Medicine, Cincinnati, OH, USA.,Division of Emergency Medicine, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Benjamin T Kerrey
- 2518University of Cincinnati, College of Medicine, Cincinnati, OH, USA.,Division of Emergency Medicine, 2518Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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12
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Murphy OC, Messacar K, Benson L, Bove R, Carpenter JL, Crawford T, Dean J, DeBiasi R, Desai J, Elrick MJ, Farias-Moeller R, Gombolay GY, Greenberg B, Harmelink M, Hong S, Hopkins SE, Oleszek J, Otten C, Sadowsky CL, Schreiner TL, Thakur KT, Van Haren K, Carballo CM, Chong PF, Fall A, Gowda VK, Helfferich J, Kira R, Lim M, Lopez EL, Wells EM, Yeh EA, Pardo CA. Acute flaccid myelitis: cause, diagnosis, and management. Lancet 2021; 397:334-346. [PMID: 33357469 PMCID: PMC7909727 DOI: 10.1016/s0140-6736(20)32723-9] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 12/20/2022]
Abstract
Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.
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Affiliation(s)
- Olwen C Murphy
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kevin Messacar
- Department of Pediatric Infectious Diseases, Children's Hospital Colorado, Aurora, CO, USA
| | - Leslie Benson
- Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Riley Bove
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
| | - Jessica L Carpenter
- Department of Neurology, Children's National Health System, Washington, DC, USA
| | - Thomas Crawford
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Janet Dean
- International Center for Spinal Cord Injury, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Roberta DeBiasi
- Department of Pediatric Infectious Diseases, Children's National Health System, Washington, DC, USA
| | - Jay Desai
- Division of Neurology, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Matthew J Elrick
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Raquel Farias-Moeller
- Department of Neurology, Children's Hospital of Wisconsin and the Medical College of Wisconsin, Milwaukee, WI, USA
| | - Grace Y Gombolay
- Department of Neurology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Benjamin Greenberg
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Matthew Harmelink
- Department of Neurology, Children's Hospital of Wisconsin and the Medical College of Wisconsin, Milwaukee, WI, USA
| | - Sue Hong
- Division of Pediatric Critical Care, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Sarah E Hopkins
- Division of Neurology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joyce Oleszek
- Department of Physical Medicine and Rehabilitation, Children's Hospital Colorado, Aurora, CO, USA
| | - Catherine Otten
- Department of Pediatric Neurology, Seattle Children's Hospital, Seattle, WA, USA
| | - Cristina L Sadowsky
- Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, USA; International Center for Spinal Cord Injury, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Teri L Schreiner
- Department of Child Neurology, Children's Hospital Colorado, Aurora, CO, USA
| | - Kiran T Thakur
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Keith Van Haren
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Carolina M Carballo
- Department of Infectious Diseases, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina
| | - Pin Fee Chong
- Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
| | - Amary Fall
- Institut Pasteur de Dakar, Département de Virologie, Dakar, Senegal
| | - Vykuntaraju K Gowda
- Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India
| | - Jelte Helfferich
- Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Ryutaro Kira
- Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
| | - Ming Lim
- Children's Neuroscience Center, Evelina London Children's Hospital, Guy's and St Thomas' NHS Trust, and Faculty of Life Sciences, King's College, London, UK
| | - Eduardo L Lopez
- Department of Infectious Diseases, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina
| | - Elizabeth M Wells
- Department of Neurology, Children's National Health System, Washington, DC, USA
| | - E Ann Yeh
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, ON, Canada
| | - Carlos A Pardo
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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13
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Howson-Wells HC, Winckles S, Aliker C, Tarr AW, Irving WL, Clark G, McClure CP. Enterovirus subtyping in a routine UK laboratory setting between 2013 and 2017. J Clin Virol 2020; 132:104646. [PMID: 32979770 DOI: 10.1016/j.jcv.2020.104646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Human enteroviruses (EV) are the leading cause of viral meningitis. EV genotyping is predominantly performed through amplification and sequencing of viral capsid protein-1 (VP1), frequently by national reference laboratories (NRLs). OBJECTIVE To determine the frequency of genotyping failure in our NRL-submitted samples and apply a superior alternative assay to resolve untyped specimens. STUDY DESIGN We initially audited genotyping data received for a cohort of patients in the East Midlands, UK by the NRL between 2013 and 2017, then identified an alternative RT-PCR typing method by literature review and evaluated primers from both assays in silico against comprehensive publicly available genomic data. The alternative assay was further optimised and applied to archived nucleic acids from previously untypable samples. RESULTS Genotyping data showed a significant increase in untypable EV strains through the study period (p = 0.0073). Typing failure appeared unrelated to sample type or viral load. In silico analyses of 2,201 EV genomes showed high levels of mismatch between reference assay primers and clinically significant EV-species, in contrast to a selected alternative semi-nested RT-PCR VP1-typing assay. This alternative assay, with minor modifications, successfully genotyped 23 of 24 previously untypable yet viable archived specimens (EV-A, n = 4; EV-B, n = 19). Phylogenetic analyses identified no predominant strain within NRL untypable isolates, suggesting sub-optimal reference assay sensitivity across EV species, in agreement with in silico analyses. CONCLUSION This modified highly sensitive RT-PCR assay presents a suitable alternative to the current English national reference VP1-typing assay and is recommended in other settings experiencing typing failure.
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Affiliation(s)
- Hannah C Howson-Wells
- Clinical Microbiology, Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, United Kingdom
| | - Stephen Winckles
- Life Sciences, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
| | - Camille Aliker
- Life Sciences, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
| | - Alexander W Tarr
- Life Sciences, University of Nottingham, Nottingham, NG7 2UH, United Kingdom; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, United Kingdom
| | - William L Irving
- Clinical Microbiology, Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, United Kingdom; Life Sciences, University of Nottingham, Nottingham, NG7 2UH, United Kingdom; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, United Kingdom
| | - Gemma Clark
- Clinical Microbiology, Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, United Kingdom
| | - C Patrick McClure
- Life Sciences, University of Nottingham, Nottingham, NG7 2UH, United Kingdom; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, United Kingdom.
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14
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Pellegrinelli L, Giardina F, Lunghi G, Uceda Renteria SC, Greco L, Fratini A, Galli C, Piralla A, Binda S, Pariani E, Baldanti F. Emergence of divergent enterovirus (EV) D68 sub-clade D1 strains, northern Italy, September to October 2018. ACTA ACUST UNITED AC 2020; 24. [PMID: 30782269 PMCID: PMC6381661 DOI: 10.2807/1560-7917.es.2018.24.7.1900090] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Between September and October 2018, an enterovirus D68 (EV-D68) outbreak occurred in patients hospitalised with severe acute respiratory infection in northern Italy; 21 laboratory-confirmed cases were reported. Phylogenetic analysis revealed that 16/20 of the EV-D68 sequences belonged to a divergent group within the sub-clade D1. Since its upsurge, EV-D68 has undergone rapid evolution with the emergence of new viral variants, emphasising the need for molecular surveillance that include outpatients with respiratory illness.
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Affiliation(s)
- Laura Pellegrinelli
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Federica Giardina
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Giovanna Lunghi
- Microbiology and Virology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Letizia Greco
- Microbiology and Virology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Alice Fratini
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Cristina Galli
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Antonio Piralla
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Sandro Binda
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Elena Pariani
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Fausto Baldanti
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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15
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Gong L, Wang Y, Zhang W, Chen C, Yang X, Xu L, Zhao C, Jiang L, Yuan Z, Xia Z, Jiang P, Ge Q, Yan J, Sun Y, Chen Y, Zhao Z, Zhang Y, Gao F. Acute Flaccid Myelitis in Children in Zhejiang Province, China. Front Neurol 2020; 11:360. [PMID: 32528396 PMCID: PMC7256184 DOI: 10.3389/fneur.2020.00360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/14/2020] [Indexed: 01/16/2023] Open
Abstract
In July-December 2018, an outbreak of polio-like acute flaccid myelitis (AFM) occurred in Zhejiang province, China. Enterovirus (EV)-D68 infection has been reported to be associated with AFM. This study aimed to investigate the clinical presentation, laboratory findings, and outcomes of AFM patients. We investigated the clinical and virologic information regarding the AFM patients, and real-time PCR, sequencing, and phylogenetic analysis were used to investigate the cause of AFM. Eighteen cases met the definition of AFM, with a median age of 4.05 years (range, 0.9-9 years), and nine (50%) were EV-D68 positive. Symptoms included acute flaccid limb weakness and cranial nerve dysfunction. On magnetic resonance imaging, 11 (61.1%) patients had spinal gray matter abnormalities. Electromyography results of 16 out of 17 patients (94.1%) were abnormal. Cerebrospinal fluid (CSF) pleocytosis was common (94.4%), while CSF protein concentration was normal in all patients. There was little improvement after early aggressive therapy. Phylogenetic analysis revealed that EV-D68 subclade B3 was the predominant lineage circulating in Zhejiang province in 2018.
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Affiliation(s)
- Liming Gong
- Zhejiang Provincial Centre for Disease Control and Prevention, Hangzhou, China
| | - Yilong Wang
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Weiqing Zhang
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Chen Chen
- Zhejiang Provincial Centre for Disease Control and Prevention, Hangzhou, China
| | - Xinghui Yang
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Lu Xu
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Congying Zhao
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Lihua Jiang
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Zhefeng Yuan
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Zhezhi Xia
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Peifang Jiang
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Qiong Ge
- Zhejiang Provincial Centre for Disease Control and Prevention, Hangzhou, China
| | - Juying Yan
- Zhejiang Provincial Centre for Disease Control and Prevention, Hangzhou, China
| | - Yi Sun
- Zhejiang Provincial Centre for Disease Control and Prevention, Hangzhou, China
| | - Yin Chen
- Zhejiang Provincial Centre for Disease Control and Prevention, Hangzhou, China
| | - Zhengyan Zhao
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Yanjun Zhang
- Zhejiang Provincial Centre for Disease Control and Prevention, Hangzhou, China
| | - Feng Gao
- Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
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16
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Cortese MM, Kambhampati AK, Schuster JE, Alhinai Z, Nelson GR, Guzman Perez-Carrillo GJ, Vossough A, Smit MA, McKinstry RC, Zinkus T, Moore KR, Rogg JM, Candee MS, Sejvar JJ, Hopkins SE. A ten-year retrospective evaluation of acute flaccid myelitis at 5 pediatric centers in the United States, 2005-2014. PLoS One 2020; 15:e0228671. [PMID: 32053652 PMCID: PMC7018000 DOI: 10.1371/journal.pone.0228671] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 01/20/2020] [Indexed: 12/18/2022] Open
Abstract
Background Acute flaccid myelitis (AFM) is a severe illness similar to paralytic poliomyelitis. It is unclear how frequently AFM occurred in U.S. children after poliovirus elimination. In 2014, an AFM cluster was identified in Colorado, prompting passive US surveillance that yielded 120 AFM cases of unconfirmed etiology. Subsequently, increased reports were received in 2016 and 2018. To help inform investigations on causality of the recent AFM outbreaks, our objective was to determine how frequently AFM had occurred before 2014, and if 2014 cases had different characteristics. Methods We conducted a retrospective study covering 2005–2014 at 5 pediatric centers in 3 U.S. regions. Possible AFM cases aged ≤18 years were identified by searching discharge ICD-9 codes and spinal cord MRI reports (>37,000). Neuroradiologists assessed MR images, and medical charts were reviewed; possible cases were classified as AFM, not AFM, or indeterminate. Results At 5 sites combined, 26 AFM cases were identified from 2005–2013 (average annual number, 3 [2.4 cases/100,000 pediatric hospitalizations]) and 18 from 2014 (12.6 cases/100,000 hospitalizations; Poisson exact p<0.0001). A cluster of 13 cases was identified in September–October 2014 (temporal scan p = 0.0001). No other temporal or seasonal trend was observed. Compared with cases from January 2005–July 2014 (n = 29), cases from August–December 2014 (n = 15) were younger (p = 0.002), more frequently had a preceding respiratory/febrile illness (p = 0.03), had only upper extremities involved (p = 0.008), and had upper extremity monoplegia (p = 0.03). The cases had higher WBC counts in cerebrospinal fluid (p = 0.013). Conclusion Our data support emergence of AFM in 2014 in the United States, and those cases demonstrated distinctive features compared with preceding sporadic cases.
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Affiliation(s)
- Margaret M. Cortese
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
- * E-mail:
| | - Anita K. Kambhampati
- Contracting Agency to the Division of Viral Diseases, IHRC, Inc., Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Jennifer E. Schuster
- Division of Infectious Diseases, Department of Pediatrics, Children’s Mercy Kansas City, Kansas City, Missouri, United States of America
| | - Zaid Alhinai
- Division of Infectious Diseases, Department of Pediatrics, Alpert Medical School, Hasbro Children’s Hospital, Brown University, Providence, Rhode Island, United States of America
| | - Gary R. Nelson
- Division of Child Neurology, Department of Pediatrics, Primary Children’s Hospital, University of Utah, Salt Lake City, Utah, United States of America
| | - Gloria J. Guzman Perez-Carrillo
- Neuroradiology Section, Mallinckrodt Institute of Radiology, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Arastoo Vossough
- Department of Radiology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Michael A. Smit
- Division of Infectious Diseases, Department of Pediatrics, Alpert Medical School, Hasbro Children’s Hospital, Brown University, Providence, Rhode Island, United States of America
| | - Robert C. McKinstry
- Neuroradiology Section, Mallinckrodt Institute of Radiology, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Timothy Zinkus
- Department of Radiology, Children’s Mercy Kansas City, Kansas City, Missouri, United States of America
| | - Kevin R. Moore
- Department of Medical Imaging, Primary Children’s Hospital, University of Utah, Salt Lake City, Utah, United States of America
| | - Jeffrey M. Rogg
- Department of Diagnostic Imaging, Alpert Medical School, Hasbro Children’s Hospital, Brown University, Providence, Rhode Island, United States of America
| | - Meghan S. Candee
- Division of Child Neurology, Department of Pediatrics, Primary Children’s Hospital, University of Utah, Salt Lake City, Utah, United States of America
| | - James J. Sejvar
- Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Sarah E. Hopkins
- Division of Neurology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
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17
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Ayers T, Lopez A, Lee A, Kambhampati A, Nix WA, Henderson E, Rogers S, Weldon WC, Oberste MS, Sejvar J, Hopkins SE, Pallansch MA, Routh JA, Patel M. Acute Flaccid Myelitis in the United States: 2015-2017. Pediatrics 2019; 144:peds.2019-1619. [PMID: 31591135 DOI: 10.1542/peds.2019-1619] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2019] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Acute flaccid myelitis (AFM) is a neurologic condition characterized by flaccid limb weakness. After a large number of reports of AFM in 2014, the Centers for Disease Control and Prevention began standardized surveillance in the United States to characterize the disease burden and explore potential etiologies and epidemiologic associations. METHODS Persons meeting the clinical case criteria of acute flaccid limb weakness from January 1, 2015, through December 31, 2017, were classified as confirmed (spinal cord gray matter lesions on MRI) or probable (white blood cell count >5 cells per mm3 in cerebrospinal fluid [CSF]). We describe clinical, radiologic, laboratory, and epidemiologic findings of pediatric patients (age ≤21 years) confirmed with AFM. RESULTS Of 305 children reported from 43 states, 193 were confirmed and 25 were probable. Of confirmed patients, 61% were male, with a median age of 6 years (range: 3 months to 21 years; interquartile range: 3 to 10 years). An antecedent respiratory or febrile illness was reported in 79% with a median of 5 days (interquartile range: 2 to 7 days) before limb weakness. Among 153 sterile-site specimens (CSF and serum) submitted to the Centers for Disease Control and Prevention, coxsackievirus A16 was detected in CSF and serum of one case patient and enterovirus D68 was detected in serum of another. Of 167 nonsterile site (respiratory and stool) specimens, 28% tested positive for enterovirus or rhinovirus. CONCLUSIONS AFM surveillance data suggest a viral etiology, including enteroviruses. Further study is ongoing to better characterize the etiology, pathogenesis, and risk factors of this rare condition.
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Affiliation(s)
- Tracy Ayers
- Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia; and
| | - Adriana Lopez
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases
| | - Adria Lee
- IHRC Inc. contracting agency to the Division of Viral Diseases
| | | | - W Allan Nix
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases
| | - Elizabeth Henderson
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases
| | - Shannon Rogers
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases
| | - William C Weldon
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases
| | - M Steven Oberste
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases
| | - James Sejvar
- Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, and
| | - Sarah E Hopkins
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Mark A Pallansch
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases
| | - Janell A Routh
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases
| | - Manisha Patel
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases,
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18
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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; 10:mBio.02262-18. [PMID: 30670612 PMCID: PMC6343034 DOI: 10.1128/mbio.02262-18] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
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. 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.
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19
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Twenty-nine Cases of Enterovirus-D68-associated Acute Flaccid Myelitis in Europe 2016: A Case Series and Epidemiologic Overview. Pediatr Infect Dis J 2019; 38:16-21. [PMID: 30234793 PMCID: PMC6296836 DOI: 10.1097/inf.0000000000002188] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Enterovirus-D68 (EV-D68) is a respiratory virus within the genus Enterovirus and the family of Picornaviridae. Genetically, it is closely related to rhinovirus that replicates in the respiratory tract and causes respiratory disease. Since 2014, EV-D68 has been associated with the neurologic syndrome of acute flaccid myelitis (AFM). METHODS In October 2016, questionnaires were sent out to a European network including 66 virologists and clinicians, to develop an inventory of EV-D68-associated AFM cases in Europe. Clinical and virologic information of case patients was requested. In addition, epidemiologic information on EV testing was collected for the period between March and October 2016. RESULTS Twenty-nine cases of EV-D68-associated AFM were identified, from 12 different European countries. Five originated from France, 5 from Scotland and 3 each from Sweden, Norway and Spain. Twenty-six were children (median age 3.8 years), 3 were adults. EV-D68 was detected in respiratory materials (n = 27), feces (n = 8) and/or cerebrospinal fluid (n = 2). Common clinical features were asymmetric flaccid limb weakness, cranial nerve deficits and bulbar symptoms. On magnetic resonance imaging, typical findings were hyperintensity of the central cord and/or brainstem; low motor amplitudes with normal conduction velocities were seen on electromyography. Full clinical recovery was rare (n = 3), and 2 patients died. The epidemiologic data from 16 European laboratories showed that of all EV-D68-positive samples, 99% was detected in a respiratory specimen. CONCLUSIONS For 2016, 29 EV-D68-related AFM cases were identified in mostly Western Europe. This is likely an underestimation, because case identification is dependent on awareness among clinicians, adequate viral diagnostics on respiratory samples and the capability of laboratories to type EVs.
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Cassidy H, Poelman R, Knoester M, Van Leer-Buter CC, Niesters HGM. Enterovirus D68 - The New Polio? Front Microbiol 2018; 9:2677. [PMID: 30483226 PMCID: PMC6243117 DOI: 10.3389/fmicb.2018.02677] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/19/2018] [Indexed: 12/20/2022] Open
Abstract
Enterovirus D68 (EV-D68) has emerged over the recent years, with large outbreaks worldwide. Increased occurrence has coincided with improved clinical awareness and surveillance of non-polio enteroviruses. Studies showing its neurotropic nature and the change in pathogenicity have established EV-D68 as a probable cause of Acute Flaccid Myelitis (AFM). The EV-D68 storyline shows many similarities with poliovirus a century ago, stimulating discussion whether EV-D68 could be ascertaining itself as the "new polio." Increasing awareness amongst clinicians, incorporating proper diagnostics and integrating EV-D68 into accessible surveillance systems in a way that promotes data sharing, will be essential to reveal the burden of disease. This will be a necessary step in preventing EV-D68 from becoming a threat to public health.
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Affiliation(s)
| | | | | | | | - Hubert G. M. Niesters
- Department of Medical Microbiology and Infection Prevention, Division of Clinical Virology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Messacar K, Asturias EJ, Hixon AM, Van Leer-Buter C, Niesters HGM, Tyler KL, Abzug MJ, Dominguez SR. Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality. THE LANCET. INFECTIOUS DISEASES 2018; 18:e239-e247. [PMID: 29482893 PMCID: PMC6778404 DOI: 10.1016/s1473-3099(18)30094-x] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/19/2017] [Accepted: 11/09/2017] [Indexed: 01/11/2023]
Abstract
Increased circulation of enterovirus D68 in 2014 and 2016 temporally and geographically coincided with increases in cases of acute flaccid myelitis, an uncommon condition of paralysis due to lesions in the anterior horn of the spinal cord. The identification of enterovirus D68 in respiratory specimens from cases of acute flaccid myelitis worldwide further supports an association, yet the absence of direct virus isolation from affected tissues, infrequent detection in cerebrospinal fluid, and the absence, until recently, of an animal model has left the causal nature of the relationship unproven. In this Personal View we evaluate epidemiological and biological evidence linking enterovirus D68 and acute flaccid myelitis. We applied the Bradford Hill criteria to investigate the evidence for a causal relationship and highlight the importance of comprehensive surveillance and research to further characterise the role of enterovirus D68 in acute flaccid myelitis and pursue effective therapies and prevention strategies.
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Affiliation(s)
- Kevin Messacar
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA; Children's Hospital Colorado, Aurora, CO, USA.
| | - Edwin J Asturias
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Children's Hospital Colorado, Aurora, CO, USA; Center for Global Health and Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
| | - Alison M Hixon
- University of Colorado School of Medicine Medical Scientist Training Program, Aurora, CO, USA
| | - Coretta Van Leer-Buter
- Division of Clinical Virology, Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Hubert G M Niesters
- Division of Clinical Virology, Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Kenneth L Tyler
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mark J Abzug
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Children's Hospital Colorado, Aurora, CO, USA
| | - Samuel R Dominguez
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Children's Hospital Colorado, Aurora, CO, USA
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