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Itagaki T, Komabayashi K, Sasaki M, Ogawa N, Seto J, Aoki Y, Ikeda T, Matsuzaki Y, Mizuta K. Seroprevalence of enterovirus D68 in Yamagata, Japan, between 1976 and 2019. J Med Virol 2024; 96:e29947. [PMID: 39370858 DOI: 10.1002/jmv.29947] [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: 05/27/2024] [Revised: 09/12/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024]
Abstract
To clarify the epidemiology of enterovirus D68 (EV-D68), an enterovirus rarely identified in the 20th century, we performed seroepidemiological analysis against EV-D68 using sera collected in 1976, 1985, 1990, 1999, 2009, and 2019, as well as Yamagata isolate (EVD68/Yamagata.JPN/2023-89), in Yamagata, Japan. The neutralizing antibody (Ab)-positive rates for those under 20 years old were 61.0%, 82.5%, 84.3%, 46.7%, 50.5%, and 67.9%, in each year, whereas the rates for those above 20 years old were between 93.4% and 99.1%. Generally, geometric mean titers (GMTs）increased with age among children and the total GMT in each year was 25.4, 49.2, 37.2, 30.8, 29.5, and 33.9, from 1976 to 2019, respectively. The findings in this Yamagata-based study showed that the seroprevalence of EV-D68 over the last four decades has increased with age among children, as a susceptible group, and then reaches a plateau of over approximately 80% among adults. This study clearly revealed that EV-D68 was stably transmitted among children in the 20th century, when EV-D68 detection was quite rare.
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Affiliation(s)
| | - Kenichi Komabayashi
- Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata, Japan
| | - Mika Sasaki
- Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata, Japan
| | - Naomi Ogawa
- Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata, Japan
| | - Junji Seto
- Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata, Japan
| | - Yoko Aoki
- Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata, Japan
| | - Tatsuya Ikeda
- Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata, Japan
| | - Yoko Matsuzaki
- Department of Infectious Diseases, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Katsumi Mizuta
- Department of Microbiology, Yamagata Prefectural Institute of Public Health, Yamagata, Japan
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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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Yoshida K, Muramatsu M, Shimizu H. Neutralizing activity of intravenous immune globulin products against enterovirus D68 strains isolated in Japan. BMC Infect Dis 2023; 23:481. [PMID: 37464326 PMCID: PMC10394975 DOI: 10.1186/s12879-023-08429-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/28/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Enterovirus D68 (EV-D68), belonging to Enterovirus D, is a unique human enterovirus mainly associated with common respiratory diseases. However, EV-D68 can cause severe respiratory diseases, and EV-D68 endemic is epidemiologically linked to current global epidemic of acute flaccid myelitis. METHODS In this study, we measured neutralizing antibody titers against six clinical EV-D68 isolates in nine intravenous immune globulin (IVIG) products commercially available in Japan to assess their potential as therapeutic options for severe EV-D68 infection. RESULTS Seven IVIG products manufactured from Japanese donors contained high neutralizing antibody titers (IC50 = 0.22-85.01 µg/mL) against all six EV-D68 strains. Apparent differences in neutralizing titers among the six EV-D68 strains were observed for all IVIG products derived from Japanese and non-Japanese blood donors. CONCLUSIONS High levels of EV-D68-neutralizing antibodies in IVIG products manufactured from Japanese donors suggest that anti-EV-D68 antibodies are maintained in the Japanese donor population similarly as found in foreign blood donors. Apparent differences in neutralizing antibody titers against the six EV-D68 strains suggest distinct antigenicity among the strains used in this study regardless of the genetic similarity of EV-D68.
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Affiliation(s)
- Kazuhiro Yoshida
- Department of Virology 2, National Institute of Infectious Diseases, Tokyo, Japan.
| | - Masamichi Muramatsu
- Department of Virology 2, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Infectious Disease Research, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
| | - Hiroyuki Shimizu
- Department of Virology 2, National Institute of Infectious Diseases, Tokyo, Japan
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Fall A, Kenmoe S, Ebogo-Belobo JT, Mbaga DS, Bowo-Ngandji A, Foe-Essomba JR, Tchatchouang S, Amougou Atsama M, Yéngué JF, Kenfack-Momo R, Feudjio AF, Nka AD, Mbongue Mikangue CA, Taya-Fokou JB, Magoudjou-Pekam JN, Noura EA, Zemnou-Tepap C, Meta-Djomsi D, Maïdadi-Foudi M, Kame-Ngasse GI, Nyebe I, Djukouo LG, Kengne Gounmadje L, Tchami Ngongang D, Oyono MG, Demeni Emoh CP, Tazokong HR, Mahamat G, Kengne-Ndé C, Sadeuh-Mba SA, Dia N, La Rosa G, Ndip L, Njouom R. Global prevalence and case fatality rate of Enterovirus D68 infections, a systematic review and meta-analysis. PLoS Negl Trop Dis 2022; 16:e0010073. [PMID: 35134062 PMCID: PMC8824346 DOI: 10.1371/journal.pntd.0010073] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 12/08/2021] [Indexed: 11/23/2022] Open
Abstract
A substantial amount of epidemiological data has been reported on Enterovirus D68 (EV-D68) infections after the 2014 outbreak. Our goal was to map the case fatality rate (CFR) and prevalence of current and past EV-D68 infections. We conducted a systematic review (PROSPERO, CRD42021229255) with published articles on EV-68 infections in PubMed, Embase, Web of Science and Global Index Medicus up to January 2021. We determined prevalences using a model random effect. Of the 4,329 articles retrieved from the databases, 89 studies that met the inclusion criteria were from 39 different countries with apparently healthy individuals and patients with acute respiratory infections, acute flaccid myelitis and asthma-related diseases. The CFR estimate revealed occasional deaths (7/1353) related to EV-D68 infections in patients with severe acute respiratory infections. Analyses showed that the combined prevalence of current and past EV-D68 infections was 4% (95% CI = 3.1-5.0) and 66.3% (95% CI = 40.0-88.2), respectively. The highest prevalences were in hospital outbreaks, developed countries, children under 5, after 2014, and in patients with acute flaccid myelitis and asthma-related diseases. The present study shows sporadic deaths linked to severe respiratory EV-D68 infections. The study also highlights a low prevalence of current EV-D68 infections as opposed to the existence of EV-D68 antibodies in almost all participants of the included studies. These findings therefore highlight the need to implement and/or strengthen continuous surveillance of EV-D68 infections in hospitals and in the community for the anticipation of the response to future epidemics.
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Affiliation(s)
- Amary Fall
- Virology Department, Institute Pasteur of Dakar, Dakar, Senegal
| | - Sebastien Kenmoe
- Virology Department, Centre Pasteur of Cameroon, Yaounde, Cameroon
- Department of Microbiology and Parasitology, University of Buea, Buea, Cameroon
| | - Jean Thierry Ebogo-Belobo
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde, Cameroon
| | | | - Arnol Bowo-Ngandji
- Department of Microbiology, The University of Yaounde I, Yaounde, Cameroon
| | | | | | - Marie Amougou Atsama
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institut de Recherches Médicales et d’Etudes des Plantes Médicinales, Yaounde, Cameroon
| | | | - Raoul Kenfack-Momo
- Department of Biochemistry, The University of Yaounde I, Yaounde, Cameroon
| | | | - Alex Durand Nka
- Virology Laboratory, Chantal Biya International Reference Center for Research on HIV/AIDS Prevention and Management, Yaounde, Cameroon
| | | | | | | | - Efietngab Atembeh Noura
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde, Cameroon
| | | | - Dowbiss Meta-Djomsi
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institut de Recherches Médicales et d’Etudes des Plantes Médicinales, Yaounde, Cameroon
| | - Martin Maïdadi-Foudi
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institut de Recherches Médicales et d’Etudes des Plantes Médicinales, Yaounde, Cameroon
| | - Ginette Irma Kame-Ngasse
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde, Cameroon
| | - Inès Nyebe
- Department of Microbiology, The University of Yaounde I, Yaounde, Cameroon
| | | | | | | | - Martin Gael Oyono
- Department of Animals Biology and Physiology, The University of Yaounde I, Yaounde, Cameroon
| | | | | | - Gadji Mahamat
- Department of Microbiology, The University of Yaounde I, Yaounde, Cameroon
| | - Cyprien Kengne-Ndé
- Research Monitoring and Planning Unit, National Aids Control Committee, Douala, Cameroon
| | | | - Ndongo Dia
- Virology Department, Institute Pasteur of Dakar, Dakar, Senegal
| | - Giuseppina La Rosa
- Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy
| | - Lucy Ndip
- Department of Microbiology and Parasitology, University of Buea, Buea, Cameroon
| | - Richard Njouom
- Virology Department, Centre Pasteur of Cameroon, Yaounde, Cameroon
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Zhang Y, Wang SY, Guo DZ, Pan SY, Lv Y. Acute flaccid paralysis and neurogenic respiratory failure associated with enterovirus D68 infection in children: Report of two cases. World J Clin Cases 2021; 9:3327-3333. [PMID: 34002141 PMCID: PMC8107912 DOI: 10.12998/wjcc.v9.i14.3327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/24/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute flaccid paralysis (AFP) and neurogenic respiratory failure rarely occur in children. At the end of 2018, some children with such symptoms were admitted to our hospital. In this study, we aimed to assess two children with AFP and neurogenic respiratory failure associated with enterovirus D68 (EV-D68).
CASE SUMMARY Two children admitted to our hospital presented with symptoms and imaging results different from those of acute disseminated encephalomyelitis and hand, foot, and mouth disease. Their main symptoms were AFP and neurogenic respiratory failure. Magnetic resonance imaging showed severe inflammatory injury mainly to the anterior horn cells of the spinal cord. Blood and cerebrospinal fluid samples were collected to assess for pathogens, including bacteria, tuberculosis, cryptococcus, herpes virus, and coxsackie virus, and the results were negative. At the beginning, the two cases were not assessed for EV-D68 in the nasopharyngeal, blood, and cerebrospinal fluid specimens. About 2 mo later, EV-D68 was detected in the stool sample of one of the cases. The symptom of AFP was caused by injury to the anterior horn cells at levels C5-L5 of the spinal cord, while neurogenic respiratory failure was at levels C3-C5.
CONCLUSION We should pay attention to the detection and diagnosis of EV-D68 and make efforts to develop antivirus drugs and vaccines.
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Affiliation(s)
- Yv Zhang
- Department of Hyperbaric Oxygen, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Sheng-Yuan Wang
- Department of Hyperbaric Oxygen, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Da-Zhi Guo
- Department of Hyperbaric Oxygen, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Shu-Yi Pan
- Department of Hyperbaric Oxygen, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Yan Lv
- Department of Hyperbaric Oxygen, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
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Zhu P, Chen S, Zhang W, Duan G, Jin Y. Essential Role of Non-Coding RNAs in Enterovirus Infection: From Basic Mechanisms to Clinical Prospects. Int J Mol Sci 2021; 22:2904. [PMID: 33809362 PMCID: PMC7999384 DOI: 10.3390/ijms22062904] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 12/31/2022] Open
Abstract
Enteroviruses (EVs) are common RNA viruses that can cause various types of human diseases and conditions such as hand, foot, and mouth disease (HFMD), myocarditis, meningitis, sepsis, and respiratory disorders. Although EV infections in most patients are generally mild and self-limiting, a small number of young children can develop serious complications such as encephalitis, acute flaccid paralysis, myocarditis, and cardiorespiratory failure, resulting in fatalities. Established evidence has suggested that certain non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) are involved in the occurrence and progression of many human diseases. Recently, the involvement of ncRNAs in the course of EV infection has been reported. Herein, the authors focus on recent advances in the understanding of ncRNAs in EV infection from basic viral pathogenesis to clinical prospects, providing a reference basis and new ideas for disease prevention and research directions.
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Affiliation(s)
- Peiyu Zhu
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (P.Z.); (S.C.); (W.Z.); (G.D.)
| | - Shuaiyin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (P.Z.); (S.C.); (W.Z.); (G.D.)
| | - Weiguo Zhang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (P.Z.); (S.C.); (W.Z.); (G.D.)
- Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Guangcai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (P.Z.); (S.C.); (W.Z.); (G.D.)
| | - Yuefei Jin
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (P.Z.); (S.C.); (W.Z.); (G.D.)
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7
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Enterovirus D68 Protease 2A pro Targets TRAF3 To Subvert Host Innate Immune Responses. J Virol 2021; 95:JVI.01856-20. [PMID: 33148796 DOI: 10.1128/jvi.01856-20] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/26/2020] [Indexed: 01/09/2023] Open
Abstract
Human enterovirus D68 (EV-D68) has received considerable attention recently as a global reemergent pathogen because it causes severe respiratory tract infections and acute flaccid myelitis (AFM). The nonstructural protein 2A protease (2Apro) of EVs, which functions in the cleavage of host proteins, comprises a pivotal part of the viral immune evasion process. However, the pathogenic mechanism of EV-D68 is not fully understood. In this study, we found that EV-D68 inhibited antiviral type I interferon responses by cleaving tumor necrosis factor receptor-associated factor 3 (TRAF3), which is the key factor for type I interferon production. EV-D68 inhibited Sendai virus (SEV)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon (IFN-β) expression in HeLa and HEK293T cells. Furthermore, we demonstrated that EV-D68 and 2Apro were able to cleave the C-terminal region of TRAF3 in HeLa and HEK293T cells, respectively. A cysteine-to-alanine substitution at amino acid 107 (C107A) in the 2Apro protease resulted in the loss of cleavage activity to TRAF3, and mutation of glycine at amino acid 462 to alanine (G462A) in TRAF3 conferred resistance to 2Apro These results suggest that control of TRAF3 by 2Apro may be a mechanism EV-D68 utilizes to subvert host innate immune responses.IMPORTANCE Human enterovirus 68 (EV-D68) has received considerable attention recently as a global reemergent pathogen because it causes severe respiratory tract infections and acute flaccid myelitis. The nonstructural protein 2A protease (2Apro) of EV, which functions in cleavage of host proteins, comprises an essential part of the viral immune evasion process. However, the pathogenic mechanism of EV-D68 is not fully understood. Here, we show for the first time that EV-D68 inhibited antiviral type I interferon responses by cleaving tumor necrosis factor receptor-associated factor 3 (TRAF3). Furthermore, we identified the key cleavage site in TRAF3. Our study may suggest a new mechanism by which the 2Apro of EV facilitates subversion of host innate immune responses. These findings increase our understanding of EV-D68 infection and may help identify new antiviral targets against EV-D68.
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Mozhgani SH, Keshavarz M, Mousavi N, Namdari H, Salimi V, Mokhtari-Azad T, Zarei-Ghobadi M, Nadji SA, Ghavami N, Rezaei F. Frequent detection of enterovirus D68 and rhinovirus type C in children with acute respiratory infections. Eur J Clin Microbiol Infect Dis 2020; 40:637-642. [PMID: 33011904 DOI: 10.1007/s10096-020-04051-y] [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: 04/13/2020] [Accepted: 09/24/2020] [Indexed: 11/27/2022]
Abstract
This study aimed to evaluate the prevalence of human rhinoviruses (HRVs) and the emergence of enterovirus D68 (EV-D68) in children. A total of 322 nasopharyngeal swab samples were provided from children with an initial diagnosis of upper and lower respiratory tract infections. A total of 34 and 70 cases were positive for EV-D68 and HRV, respectively. The phylogenetic analysis revealed that the clades A and B are the prevalent genotypes for EV-D68 and the HRV-positive samples belong to three types including HRV-A, HRV-B, and HRV-C. The results showed that EV-D68 and HRV-C are circulating in Iran especially in the winter.
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Affiliation(s)
- Sayed-Hamidreza Mozhgani
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Mohsen Keshavarz
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Neda Mousavi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran
| | - Haideh Namdari
- Iranian Tissue Bank and Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran
| | - Talat Mokhtari-Azad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran
| | | | - Seyed Alireza Nadji
- Virology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nastaran Ghavami
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran
| | - Farhad Rezaei
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran.
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Pan HH, Tsai CR, Ting PJ, Huang FL, Wang LC, Lin CF, Ko JL, Lue KH, Chen PY. Respiratory presentation of patients infected with enterovirus D68 in Taiwan. Pediatr Neonatol 2020; 61:168-173. [PMID: 31575458 DOI: 10.1016/j.pedneo.2019.09.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 05/27/2019] [Accepted: 09/06/2019] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Enterovirus-D68 (EV-D68) has been endemic in Taiwan for some years with a small number of positive cases. Detailed information about respiratory presentation is lacking. This study characterized the clinical course in children admitted to the medical center and regional hospital in Taichung during 2015. METHODS Retrospective chart review of patients with confirmed EV-D68 infection admitted to the medical center and regional hospital in Taichung with respiratory symptoms in the second half of 2015. Past medical history, clinical presentation, management, and course in hospital were collected and analyzed. Simple demographic data and clinical symptoms were also collected from patients confirmed with EV-D68 infection who visited clinics in Taichung. RESULTS Six children were included. Two patients had a prior history of asthma or recurrent dyspnea, and one had other preexisting medical comorbidities. One child was admitted to the pediatric intensive care unit. All the patients were cured. Cough, rhinorrhea, tachypnea and fever were the most common clinical symptoms among inpatients, while influenza-like illness (ILI) was prevalent in outpatients. CONCLUSION EV-D68 infection resulted in respiratory presentations of asthma-like illness in the hospitalized pediatric population. Patients with a prior history of asthma or recurrent dyspnea appear to be more severely affected.
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Affiliation(s)
- Hui-Hsien Pan
- Department of Pediatrics, Chung-Shan Medical University Hospital, Taichung City, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan; School of Medicine, Chung Shan Medical University, Taichung City, Taiwan
| | - Chi-Ren Tsai
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, Taiwan
| | - Pei-Ju Ting
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, Taiwan
| | - Fang-Liang Huang
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, Taiwan; Hung Kuang University, Taichung, Taiwan
| | - Li-Chung Wang
- Microbiology Section of the Medical Laboratory Department, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chin-Fu Lin
- Microbiology Section of the Medical Laboratory Department, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jiunn-Liang Ko
- Department of Pediatrics, Chung-Shan Medical University Hospital, Taichung City, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan; Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ko-Huang Lue
- Department of Pediatrics, Chung-Shan Medical University Hospital, Taichung City, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan; School of Medicine, Chung Shan Medical University, Taichung City, Taiwan.
| | - Po-Yen Chen
- School of Medicine, Chung Shan Medical University, Taichung City, Taiwan; Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, Taiwan.
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Hixon AM, Frost J, Rudy MJ, Messacar K, Clarke P, Tyler KL. Understanding Enterovirus D68-Induced Neurologic Disease: A Basic Science Review. Viruses 2019; 11:E821. [PMID: 31487952 PMCID: PMC6783995 DOI: 10.3390/v11090821] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 08/28/2019] [Accepted: 08/29/2019] [Indexed: 12/28/2022] Open
Abstract
In 2014, the United States (US) experienced an unprecedented epidemic of enterovirus D68 (EV-D68)-induced respiratory disease that was temporally associated with the emergence of acute flaccid myelitis (AFM), a paralytic disease occurring predominantly in children, that has a striking resemblance to poliomyelitis. Although a definitive causal link between EV-D68 infection and AFM has not been unequivocally established, rapidly accumulating clinical, immunological, and epidemiological evidence points to EV-D68 as the major causative agent of recent seasonal childhood AFM outbreaks in the US. This review summarizes evidence, gained from in vivo and in vitro models of EV-D68-induced disease, which demonstrates that contemporary EV-D68 strains isolated during and since the 2014 outbreak differ from historical EV-D68 in several factors influencing neurovirulence, including their genomic sequence, their receptor utilization, their ability to infect neurons, and their neuropathogenicity in mice. These findings provide biological plausibility that EV-D68 is a causal agent of AFM and provide important experimental models for studies of pathogenesis and treatment that are likely to be difficult or impossible in humans.
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Affiliation(s)
- Alison M Hixon
- Medical Scientist Training Program, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Joshua Frost
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Michael J Rudy
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Kevin Messacar
- Hospital Medicine and Pediatric Infectious Disease Sections, Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA.
- Children's Hospital Colorado, Aurora, CO 80045, USA.
| | - Penny Clarke
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
| | - Kenneth L Tyler
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Division of Infectious Disease, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Neurology Service, Rocky Mountain VA Medical Center, Aurora, CO 80045, USA
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11
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Kadji FMN, Nishimura H, Okamoto M, Sato K, Ohmiya S, Ito H, Suzuki A, Nagai Y, Oshitani H. Fluctuations in Antibody Titers against Enterovirus D68 in Pediatric Sera Collected in a Community before, during, and after a Possible Outbreak. Jpn J Infect Dis 2019; 73:55-57. [PMID: 31474700 DOI: 10.7883/yoken.jjid.2019.056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We previously reported a hospital-based epidemiological study on enterovirus (EV)-D68 infection among children during the autumn of 2015, which indirectly inferred an outbreak in Sendai, Japan. In this study, stocked sera of children (aged 0-6 years; without symptoms of infectious diseases) in the Sendai community collected during 4 periods (1 year before, 6 months before, immediately after, and 1 year after the possible outbreak period) were analyzed using the neutralization antibody titer assay to determine community children's immunity levels against EV-D68 infection. The immunity levels were confirmed to have increased during the possible outbreak period and to have gradually waned over 1 year without another outbreak. These results provide background information supporting the results of our previous hospital-based surveillance study.
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Affiliation(s)
- Francois Marie Ngako Kadji
- Virus Research Center, Clinical Research Division, Sendai Medical Center.,Department of Virology, Tohoku University Graduate School of Medicine
| | - Hidekazu Nishimura
- Virus Research Center, Clinical Research Division, Sendai Medical Center
| | - Michiko Okamoto
- Department of Virology, Tohoku University Graduate School of Medicine
| | - Ko Sato
- Virus Research Center, Clinical Research Division, Sendai Medical Center
| | - Suguru Ohmiya
- Virus Research Center, Clinical Research Division, Sendai Medical Center
| | - Hiroko Ito
- Virus Research Center, Clinical Research Division, Sendai Medical Center
| | - Akira Suzuki
- Virus Research Center, Clinical Research Division, Sendai Medical Center.,Department of Virology, Tohoku University Graduate School of Medicine.,Miyagi Prefecture Ishinomaki Public Health Center
| | | | - Hitoshi Oshitani
- Department of Virology, Tohoku University Graduate School of Medicine
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12
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Furuse Y, Chaimongkol N, Okamoto M, Oshitani H. Evolutionary and Functional Diversity of the 5' Untranslated Region of Enterovirus D68: Increased Activity of the Internal Ribosome Entry Site of Viral Strains during the 2010s. Viruses 2019; 11:v11070626. [PMID: 31288421 PMCID: PMC6669567 DOI: 10.3390/v11070626] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/04/2019] [Accepted: 07/05/2019] [Indexed: 12/14/2022] Open
Abstract
The 5′ untranslated region (UTR) of the RNA genomes of enteroviruses possesses an internal ribosome entry site (IRES) that directs translation of the mRNA by binding to ribosomes. Infection with enterovirus D68 causes respiratory symptoms and is sometimes associated with neurological disorders. The number of reports of the viral infection and neurological disorders has increased in 2010s, although the reason behind this phenomenon remains unelucidated. In this study, we investigated the evolutionary and functional diversity of the 5′ UTR of recently circulating strains of the virus. Genomic sequences of 374 viral strains were acquired and subjected to phylogenetic analysis. The IRES activity of the viruses was measured using a luciferase reporter assay. We found a highly conserved sequence in the 5′ UTR and also identified the location of variable sites in the predicted RNA secondary structure. IRES activities differed among the strains in some cell lines, including neuronal and respiratory cells, and were especially high in strains of a major lineage from the recent surge. The effect of mutations in the 5′ UTR should be studied further in the future for better understanding of viral pathogenesis.
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Affiliation(s)
- Yuki Furuse
- Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
- Hakubi Center for Advanced Research, Kyoto University, Yoshidahonmachi, Sakyo-ku, Kyoto 606-8501, Japan.
- Department of Virology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan.
- Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, 6-3 Aramaki aza Aoba, Aoba-ku, Sendai 980-8578, Japan.
| | - Natthawan Chaimongkol
- Department of Virology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan
| | - Michiko Okamoto
- Department of Virology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan
| | - Hitoshi Oshitani
- Department of Virology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan
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13
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Mizuta K, Tanaka W, Komabayashi K, Tanaka S, Seto J, Aoki Y, Ikeda T. Longitudinal Epidemiology of Viral Infectious Diseases Combining Virus Isolation, Antigenic Analysis, and Phylogenetic Analysis as Well as Seroepidemiology in Yamagata, Japan, between 1999 and 2018. Jpn J Infect Dis 2019; 72:211-223. [PMID: 30814463 DOI: 10.7883/yoken.jjid.2018.500] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We introduced a microplate method for virus isolation in the Department of Microbiology, Yamagata Prefectural Institute of Public Health (YPIPH) in 1999 in Yamagata, Japan. We have since carried out longitudinal epidemiological studies on viral infectious diseases, particularly respiratory viruses, combining traditional technologies such as virus isolation and serological techniques and newly developed molecular methods. Here, we provide an overview of our activities at YPIPH between 1999 and 2018. During the study period, we observed emerging and re-merging diseases such as those caused by echovirus type 13, enterovirus D68, parechovirus-A3 (PeV-A3), and Saffold virus. With regard to PeV-A3, we proposed a new disease concept, "PeV-A3-associated myalgia/myositis." We also revealed the longitudinal epidemiologies of several viruses such as enterovirus A71 and coxsackievirus A16. To perform longitudinal epidemiological studies at any time in Yamagata, we established a system for stocking clinical specimens, viral isolates, complementary DNAs, and serum specimens. We have also pursued collaboration works with virology laboratories across Japan. We hope our experiences, findings, and research materials will further contribute to the development of countermeasures against viral infectious diseases and improvement in public health strategies in Yamagata, Japan, Asia, and around the world.
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Affiliation(s)
- Katsumi Mizuta
- Department of Microbiology, Yamagata Prefectural Institute of Public Health
| | - Waka Tanaka
- Department of Microbiology, Yamagata Prefectural Institute of Public Health
| | | | - Shizuka Tanaka
- Department of Microbiology, Yamagata Prefectural Institute of Public Health
| | - Junji Seto
- Department of Microbiology, Yamagata Prefectural Institute of Public Health
| | - Yoko Aoki
- Department of Microbiology, Yamagata Prefectural Institute of Public Health
| | - Tatsuya Ikeda
- Department of Microbiology, Yamagata Prefectural Institute of Public Health
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14
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Han M, Rajput C, Ishikawa T, Jarman CR, Lee J, Hershenson MB. Small Animal Models of Respiratory Viral Infection Related to Asthma. Viruses 2018; 10:E682. [PMID: 30513770 PMCID: PMC6316391 DOI: 10.3390/v10120682] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 11/21/2018] [Accepted: 11/29/2018] [Indexed: 12/20/2022] Open
Abstract
Respiratory viral infections are strongly associated with asthma exacerbations. Rhinovirus is most frequently-detected pathogen; followed by respiratory syncytial virus; metapneumovirus; parainfluenza virus; enterovirus and coronavirus. In addition; viral infection; in combination with genetics; allergen exposure; microbiome and other pathogens; may play a role in asthma development. In particular; asthma development has been linked to wheezing-associated respiratory viral infections in early life. To understand underlying mechanisms of viral-induced airways disease; investigators have studied respiratory viral infections in small animals. This report reviews animal models of human respiratory viral infection employing mice; rats; guinea pigs; hamsters and ferrets. Investigators have modeled asthma exacerbations by infecting mice with allergic airways disease. Asthma development has been modeled by administration of virus to immature animals. Small animal models of respiratory viral infection will identify cell and molecular targets for the treatment of asthma.
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Affiliation(s)
- Mingyuan Han
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Charu Rajput
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Tomoko Ishikawa
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Caitlin R Jarman
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Julie Lee
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Marc B Hershenson
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
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15
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Atomic structures of enterovirus D68 in complex with two monoclonal antibodies define distinct mechanisms of viral neutralization. Nat Microbiol 2018; 4:124-133. [PMID: 30397341 DOI: 10.1038/s41564-018-0275-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 09/24/2018] [Indexed: 02/05/2023]
Abstract
Enterovirus D68 (EV-D68) undergoes structural transformation between mature, cell-entry intermediate (A-particle) and empty forms throughout its life cycle. Structural information for the various forms and antibody-bound capsids will facilitate the development of effective vaccines and therapeutics against EV-D68 infection, which causes childhood respiratory and paralytic diseases worldwide. Here, we report the structures of three EV-D68 capsid states representing the virus at major phases. We further describe two original monoclonal antibodies (15C5 and 11G1) with distinct structurally defined mechanisms for virus neutralization. 15C5 and 11G1 engage the capsid loci at icosahedral three-fold and five-fold axes, respectively. To block viral attachment, 15C5 binds three forms of capsids, and triggers mature virions to transform into A-particles, mimicking engagement by the functional receptor ICAM-5, whereas 11G1 exclusively recognizes the A-particle. Our data provide a structural and molecular explanation for the transition of picornavirus capsid conformations and demonstrate distinct mechanisms for antibody-mediated neutralization.
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16
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Pan M, Gao S, Zhou Z, Zhang K, Liu S, Wang Z, Wang T. A reverse genetics system for enterovirus D68 using human RNA polymerase I. Virus Genes 2018; 54:484-492. [PMID: 29777445 DOI: 10.1007/s11262-018-1570-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 05/05/2018] [Indexed: 01/15/2023]
Abstract
Human enterovirus D68 (EV-D68) is a highly contagious virus, which causes respiratory tract infections. However, no effective vaccines are currently available for controlling EV-D68 infection. Here, we developed a reverse genetics system to recover EV-D68 minireplicons and infectious EV-D68 from transfected plasmids using the RNA polymerase I (Pol I) promoter. The EV-D68 minireplicons contained the luciferase reporter gene, which flanked by the non-coding regions of the EV-D68 RNA. The luciferase signals could be detected in cells after transfection and Pol I promoter-mediated luciferase signal was significantly stronger than that mediated by the T7 promoter. Furthermore, recombinant viruses were generated by transfecting plasmids that contained the genomic RNA segments of EV-D68, under the control of Pol I promoter into 293T cells or RD cells. On plaque morphology and growth kinetics, the rescued virus and parental virus were indistinguishable. In addition, we showed that the G394C mutation disrupts the viral 5'-UTR structure and suppresses the viral cap-independent translation. This reverse genetics system for EV-D68 recovery can greatly facilitate research into EV-D68 biology. Moreover, this system could accelerate the development of EV-D68 vaccines and anti-EV-D68 drugs.
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Affiliation(s)
- Minglei Pan
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China
| | - Shuai Gao
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China
| | - Zhenwei Zhou
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China
| | - Keke Zhang
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China
| | - Sihua Liu
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China
| | - Zhiyun Wang
- School of Environmental Science and Engineering, 92 Weijin Road, Nankai District, Tianjin, 300072, China.
| | - Tao Wang
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China.
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17
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Concurrent Community Transmission of Enterovirus D68 With Human Rhinoviruses and Respiratory Syncytial Virus Among Children in Sendai, Japan. Pediatr Infect Dis J 2018; 37:394-400. [PMID: 29189674 DOI: 10.1097/inf.0000000000001768] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND In the autumn of 2015, we experienced a surge in the number of pediatric cases of wheeze in our hospital, which was suspected to be caused by enterovirus (EV)-D68 transmission in the community. Thus, we implemented an ad hoc retrospective surveillance for EV-D68. METHODS Patients <15 years of age with acute respiratory infection were eligible for inclusion in this study. All enrolled patients underwent virus detection test. Additionally, neutralization tests (NTs) were performed using the stored serum samples of the enrolled patients to compare the antigenicity of the virus isolated in this study with that isolated in 2010 and evaluate the anti-EV-D68 antibody prevalence. RESULTS Respiratory syncytial virus (RSV) was the most commonly detected virus (35%), followed by EV-D68 (19%) and non-EV-D68 enteroviruses/human rhinoviruses (14%). Patients with EV-D68 infection had higher median age than those with RSV infection (P < 0.05). Moreover, patients with EV-D68 infection showed a higher expiratory wheeze prevalence than those with non-EV-D68 enterovirus/rhinovirus and RSV infections. The antigenicity of the isolate from the current study was similar to the virus that circulated in 2010. At the early study phase, children in our community did not have high NT titers, but the median log NT titer increased from 1.5 to 5 over time (P < 0.05). CONCLUSION This study showed the concurrent circulation of EV-D68 with non-EV-D68 enteroviruses/rhinoviruses and RSV in infants and children in our community and captured the early stage of EV-D68 transmission.
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18
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Piralla A, Principi N, Ruggiero L, Girello A, Giardina F, De Sando E, Caimmi S, Bianchini S, Marseglia GL, Lunghi G, Baldanti F, Esposito S. Enterovirus-D68 (EV-D68) in pediatric patients with respiratory infection: The circulation of a new B3 clade in Italy. J Clin Virol 2018; 99-100:91-96. [PMID: 29396353 PMCID: PMC7185653 DOI: 10.1016/j.jcv.2018.01.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 01/03/2018] [Accepted: 01/11/2018] [Indexed: 11/01/2022]
Abstract
BACKGROUND In recent years, several outbreaks due to Enterovirus D-68 (EV-D68) have been reported, and it was confirmed that the virus can cause upper and lower respiratory tract diseases and be associated with the development of neurological problems. OBJECTIVES The main aim of this research was to study the genetic characteristics of EV-D68 strains that were circulating in Italy identified during an outbreak of an EV-D68 infection that occurred in Italy during the period March-October 2016. STUDY DESIGN A retrospective study of the circulation of different types and subtypes of EV-D68 was performed. Nasopharyngeal swabs were collected from March 2016 through October 2016 in children admitted to the Emergency Room with respiratory diseases. RESULTS Among 390 children, 22 (59.1% males; mean age 47 months) were found to be infected by EV-D68 and most of them were immunocompetent (72.7%). Pneumonia was diagnosed in 12 (54.5%) children. Phylogenetic analysis of the VP1 region showed that all the strains identified in this study belonged to clade B3. Within B3 subclade, the Italian EV-D68 strains were most closely related to strains detected in Southern China in 2015 as well as to strains detected in US and the Netherlands in 2016. CONCLUSIONS These results showed that EV-D68 infections are a common cause of lower respiratory illness in pediatric age. The circulation of one EV-D68 lineage has been proven in Italy and in the European region during 2016. However, further studies are required to investigate whether some strains or lineages may possess a higher affinity for the lower airway or central nervous system.
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Affiliation(s)
- Antonio Piralla
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Nicola Principi
- Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy
| | - Luca Ruggiero
- Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy
| | - Alessia Girello
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Federica Giardina
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Elisabetta De Sando
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Pavia, Italy
| | - Silvia Caimmi
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Pavia, Italy
| | - Sonia Bianchini
- Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy
| | - Gian Luigi Marseglia
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Pavia, Italy
| | - Giovanna Lunghi
- Virology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pavia, Italy
| | - Fausto Baldanti
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Clinical Surgical, Diagnostic and Pediatric Sciences, Università degli Studi di Pavia, Pavia, Italy
| | - Susanna Esposito
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06129, Perugia, Italy.
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19
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Itagaki T, Aoki Y, Matoba Y, Tanaka S, Ikeda T, Mizuta K, Matsuzaki Y. Clinical characteristics of children infected with enterovirus D68 in an outpatient clinic and the association with bronchial asthma. Infect Dis (Lond) 2017; 50:303-312. [PMID: 29119851 DOI: 10.1080/23744235.2017.1400176] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND All reports of increases in severe respiratory disease associated with human enterovirus D68 (EV-D68) are from hospital settings. However, there are few reports describing clinical characteristics in less severely affected populations. METHODS We conducted a retrospective observational study from January 2010 to December 2015 in Yamagata, Japan. Using regional passive surveillance, 5794 respiratory specimens were collected from children who initially presented to an outpatient clinic with acute respiratory symptoms. The collected samples were tested for EV-D68 by reverse transcription PCR. RESULTS EV-D68 was detected in 79 specimens mainly during the two epidemic periods in August-October 2010 and August-October 2015, when detection rates were 10.2% (31 of 304 specimens) and 16.3% (46 of 282 specimens), respectively. Among the 69 EV-D68-positive children, excluding those with viral coinfection, 39 (57%) had upper respiratory tract infections, 23 (33%) bronchiolitis or asthma attack, 5 (7%) bronchitis, 1 (1%) meningitis and 1 (1%) acute flaccid paralysis. In 23 children with wheezing, retraction was observed in 10 (43%), and six (26%) were diagnosed with asthma exacerbation. Six children required hospital admission, five (83%) because of asthma exacerbation. A history of asthma or wheezing was the most significant risk factor for the development of wheezing (odds ratio, 8.23; 95% CI, 2.65-25.50; p < .001). CONCLUSIONS The low rate of hospitalization (9%, 6 of 69) indicates that most cases with EV-D68 infection were managed as outpatients. A history of asthma or wheezing was a potential risk factor for wheezing, resulting in hospitalization due to a severe asthma attack.
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Affiliation(s)
| | - Yoko Aoki
- b Department of Microbiology , Yamagata Prefectural Institute of Public Health , Tokamachi , Japan
| | - Yohei Matoba
- b Department of Microbiology , Yamagata Prefectural Institute of Public Health , Tokamachi , Japan
| | - Shizuka Tanaka
- b Department of Microbiology , Yamagata Prefectural Institute of Public Health , Tokamachi , Japan
| | - Tatsuya Ikeda
- b Department of Microbiology , Yamagata Prefectural Institute of Public Health , Tokamachi , Japan
| | - Katsumi Mizuta
- b Department of Microbiology , Yamagata Prefectural Institute of Public Health , Tokamachi , Japan
| | - Yoko Matsuzaki
- c Department of Infectious Diseases , Yamagata University Faculty of Medicine , Iida-Nishi , Japan
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20
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Kaida A, Iritani N, Yamamoto SP, Kanbayashi D, Hirai Y, Togawa M, Amo K, Kohdera U, Nishigaki T, Shiomi M, Asai S, Kageyama T, Kubo H. Distinct genetic clades of enterovirus D68 detected in 2010, 2013, and 2015 in Osaka City, Japan. PLoS One 2017; 12:e0184335. [PMID: 28902862 PMCID: PMC5597212 DOI: 10.1371/journal.pone.0184335] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 08/22/2017] [Indexed: 12/23/2022] Open
Abstract
The first upsurge of enterovirus D68 (EV-D68), a causative agent of acute respiratory infections (ARIs), in Japan was reported in Osaka City in 2010. In this study, which began in 2010, we surveyed EV-D68 in children with ARIs and analyzed sequences of EV-D68 strains detected. Real-time PCR of 19 respiratory viruses or subtypes of viruses, including enterovirus, was performed on 2,215 specimens from ARI patients (<10 years of age) collected between November 2010 and December 2015 in Osaka City, Japan. EV-D68 was identified in 18 enterovirus-positive specimens (n = 4 in 2013, n = 1 in 2014, and n = 13 in 2015) by analysis of viral protein 1 (VP1) or VP4 sequences, followed by a BLAST search for similar sequences. All EV-D68 strains were detected between June and October (summer to autumn), except for one strain detected in 2014. A phylogenetic analysis of available VP1 sequences revealed that the Osaka strains detected in 2010, 2013, and 2015 belonged to distinct clusters (Clades C, A, and B [Subclade B3], respectively). Comparison of the 5' untranslated regions of these viruses showed that Osaka strains in Clades A, B (Subclade B3), and C commonly had deletions at nucleotide positions 681-703 corresponding to the prototype Fermon strain. Clades B and C had deletions from nucleotide positions 713-724. Since the EV-D68 epidemic in 2010, EV-D68 re-emerged in Osaka City, Japan, in 2013 and 2015. Results of this study indicate that distinct clades of EV-D68 contributed to re-emergences of this virus in 2010, 2013, and 2015 in this limited region.
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Affiliation(s)
- Atsushi Kaida
- Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan
- * E-mail:
| | - Nobuhiro Iritani
- Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan
| | - Seiji P. Yamamoto
- Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan
| | - Daiki Kanbayashi
- Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan
| | - Yuki Hirai
- Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan
| | | | - Kiyoko Amo
- Osaka City General Hospital, Osaka, Japan
| | | | | | | | | | - Tsutomu Kageyama
- Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hideyuki Kubo
- Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan
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21
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Huang YP, Lin TL, Lin TH, Wu HS. Molecular and epidemiological study of enterovirus D68 in Taiwan. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2017; 50:411-417. [DOI: 10.1016/j.jmii.2015.07.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 07/25/2015] [Accepted: 07/28/2015] [Indexed: 10/23/2022]
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First Report of a Fatal Case Associated with EV-D68 Infection in Hong Kong and Emergence of an Interclade Recombinant in China Revealed by Genome Analysis. Int J Mol Sci 2017; 18:ijms18051065. [PMID: 28509856 PMCID: PMC5454976 DOI: 10.3390/ijms18051065] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 05/04/2017] [Accepted: 05/09/2017] [Indexed: 12/19/2022] Open
Abstract
A fatal case associated with enterovirus D68 (EV-D68) infection affecting a 10-year-old boy was reported in Hong Kong in 2014. To examine if a new strain has emerged in Hong Kong, we sequenced the partial genome of the EV-D68 strain identified from the fatal case and the complete VP1, and partial 5′UTR and 2C sequences of nine additional EV-D68 strains isolated from patients in Hong Kong. Sequence analysis indicated that a cluster of strains including the previously recognized A2 strains should belong to a separate clade, clade D, which is further divided into subclades D1 and D2. Among the 10 EV-D68 strains, 7 (including the fatal case) belonged to the previously described, newly emerged subclade B3, 2 belonged to subclade B1, and 1 belonged to subclade D1. Three EV-D68 strains, each from subclades B1, B3, and D1, were selected for complete genome sequencing and recombination analysis. While no evidence of recombination was noted among local strains, interclade recombination was identified in subclade D2 strains detected in mainland China in 2008 with VP2 acquired from clade A. This study supports the reclassification of subclade A2 into clade D1, and demonstrates interclade recombination between clades A and D2 in EV-D68 strains from China.
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23
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Wang G, Zhuge J, Huang W, Nolan SM, Gilrane VL, Yin C, Dimitrova N, Fallon JT. Enterovirus D68 Subclade B3 Strain Circulating and Causing an Outbreak in the United States in 2016. Sci Rep 2017; 7:1242. [PMID: 28455514 PMCID: PMC5430842 DOI: 10.1038/s41598-017-01349-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 03/24/2017] [Indexed: 11/09/2022] Open
Abstract
In 2014 the United States experienced a nationwide outbreak of Enterovirus D68 (EV-D68) infection. There were no confirmed cases of EV-D68 in 2015 and CDC was only aware of limited sporadic EV-D68 detection in the US in 2016. In this report, we analyzed 749 nasopharyngeal (NP) specimens collected in 2015 and 2016 from patients in the Lower Hudson Valley, New York using a previously validated EV-D68-specific rRT-PCR assay. EV-D68 was detected in none of 199 NP specimens collected in 2015, and in one of 108 (0.9%) samples from January to May and 159 of 442 (36.0%) samples from July to October 2016. Complete EV-D68 genome sequences from 22 patients in 2016 were obtained using a metagenomic next-generation sequencing assay. Comparative genome analysis confirmed that a new EV-D68 strain belonging to subclade B3, with 3.2-4.8% divergence in nucleotide from subclade B1 strains identified during the 2014 US outbreak, was circulating in the US in 2016 and caused an outbreak in the Lower Hudson Valley, New York with 160 laboratory-confirmed cases. Our data highlight the genetic variability and capacity in causing outbreak by diverse EV-D68 strains, and the necessity of awareness and more surveillance on their active circulation worldwide.
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Affiliation(s)
- Guiqing Wang
- Department of Pathology, New York Medical College, Valhalla, New York, USA. .,Department of Pathology and Clinical Laboratories, Westchester Medical Center, Valhalla, New York, USA.
| | - Jian Zhuge
- Department of Pathology and Clinical Laboratories, Westchester Medical Center, Valhalla, New York, USA
| | - Weihua Huang
- Department of Pathology, New York Medical College, Valhalla, New York, USA
| | - Sheila M Nolan
- Department of Pediatrics, Division of Infectious Disease, New York Medical College and Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York, USA
| | - Victoria L Gilrane
- Department of Pathology, New York Medical College, Valhalla, New York, USA
| | - Changhong Yin
- Department of Pathology, New York Medical College, Valhalla, New York, USA
| | | | - John T Fallon
- Department of Pathology, New York Medical College, Valhalla, New York, USA.,Department of Pathology and Clinical Laboratories, Westchester Medical Center, Valhalla, New York, USA
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Schuffenecker I, Mirand A, Josset L, Henquell C, Hecquet D, Pilorgé L, Petitjean-Lecherbonnier J, Manoha C, Legoff J, Deback C, Pillet S, Lepiller Q, Mansuy JM, Marque-Juillet S, Antona D, Peigue-Lafeuille H, Lina B. Epidemiological and clinical characteristics of patients infected with enterovirus D68, France, July to December 2014. ACTA ACUST UNITED AC 2017; 21:30226. [PMID: 27195770 DOI: 10.2807/1560-7917.es.2016.21.19.30226] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 02/05/2016] [Indexed: 11/20/2022]
Abstract
In 2014, the United States (US) experienced a nationwide outbreak of enterovirus D68 (EV-D68) infection with 1,152 cases reported mainly in hospitalised children with severe asthma or bronchiolitis. Following the US alert, 11 laboratories of the French enterovirus (EV) surveillance network participated in an EV-D68 survey. A total of 6,229 respiratory samples, collected from 1 July to 31 December 2014, were screened for EV-D68 resulting in 212 EV-D68-positive samples. These 212 samples corresponded to 200 EV-D68 cases. The overall EV-D68 positivity rates among respiratory samples were of 5% (184/3,645) and 1.1% (28/2,584) in hospitalised children and adults respectively. The maximum weekly EV-D68 positivity rates were of 16.1% for children (n = 24/149; week 43) and 2.6% for adults (n = 3/115; week 42). Of 173 children with EV-D68 infection alone, the main symptoms were asthma (n = 83; 48.0%) and bronchiolitis (n = 37; 21.4%). One child developed acute flaccid paralysis (AFP) following EV-D68-associated pneumonia. Although there was no significant increase in severe respiratory tract infections reported to the French public health authorities, 10.7% (19/177) of the EV-D68 infected children and 14.3% (3/21) of the EV-D68 infected adults were hospitalised in intensive care units. Phylogenetic analysis of the viral protein 1 (VP1) sequences of 179 EV-D68 cases, revealed that 117 sequences (65.4%), including that of the case of AFP, belonged to the B2 variant of clade B viruses. Continuous surveillance of EV-D68 infections is warranted and could benefit from existing influenza-like illness and EV surveillance networks.
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Affiliation(s)
- Isabelle Schuffenecker
- Centre National de Référence des Enterovirus et Parechovirus, Laboratoire de Virologie, Hospices Civils de Lyon, Lyon, France
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Bosis S, Esposito S. Enterovirus D68-Associated Community-Acquired Pneumonia in the Pediatric Age Group. Curr Infect Dis Rep 2017; 19:12. [PMID: 28251508 DOI: 10.1007/s11908-017-0567-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW This review summarizes the current knowledge regarding the role of Enterovirus D68 (EV-D68) in community-acquired pneumonia (CAP) in children. RECENT FINDINGS EV-D68 is an emergent viral pathogen. Since its first isolation in 1962 in California in four children suffering from CAP and bronchiolitis, EV-D68 has been rarely detected from respiratory specimens. However, recently, EV-D68 infection has raised concerns in the international community because of outbreaks in 2014 in the USA and the increased number of children with EV-D68-associated severe respiratory illnesses, including pneumonia, that have been reported in many other countries around the world. EV-D68 causes severe and life-threatening respiratory diseases in the pediatric population, particularly in children with underlying conditions such as prematurity or chronic diseases. Since no specific treatment or vaccinations are available for EV-D68 infections, greater surveillance as well as the use of sensitive and rapid diagnostic methods are essential to prevent and manage new outbreaks.
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Affiliation(s)
- Samantha Bosis
- Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Susanna Esposito
- Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. .,Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06129, Perugia, Italy.
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26
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Li J, Hao C, Liu X, Qin X. Differential evolutionary dynamics of Enterovirus D68 from countries of different continents. Future Virol 2017. [DOI: 10.2217/fvl-2016-0092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: To explore the underlying genetic reasons of Enterovirus D68 (EV-D68) for its differential epidemiological patterns among continents. Materials & methods: Four hundred and sixty complete VP1 sequences of EV-D68 from GenBank were analyzed with phylodynamics approaches. Results: Sharp bottlenecks of viral population dynamics in 2014 were observed to be strongly correlated with pandemic prevalence of EV-D68; multi-clade distribution of EV-D68 in the USA and Germany in the time-scaled maximum clade credibility tree of total EV-D68 was also a discriminative feature between pandemic and sporadic prevalences. Conclusion: These findings provide insights into the phylogenetic features of EV-D68 correlated with its differential epidemiological patterns among continents.
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Affiliation(s)
- Jianguo Li
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
| | - Chunyan Hao
- College of Chemical & Biological Engineering, Taiyuan University of Science & Technology, Taiyuan 030021, China
| | - Xianjun Liu
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
- College of Chemical & Biological Engineering, Taiyuan University of Science & Technology, Taiyuan 030021, China
| | - Xuemei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
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27
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Moyer K, Wang H, Salamon D, Leber A, Mejias A. Enterovirus D68 in Hospitalized Children: Sequence Variation, Viral Loads and Clinical Outcomes. PLoS One 2016; 11:e0167111. [PMID: 27875593 PMCID: PMC5119825 DOI: 10.1371/journal.pone.0167111] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 11/08/2016] [Indexed: 12/11/2022] Open
Abstract
Background An outbreak of enterovirus D68 (EV-D68) caused severe respiratory illness in 2014. The disease spectrum of EV-D68 infections in children with underlying medical conditions other than asthma, the role of EV-D68 loads on clinical illness, and the variation of EV-D68 strains within the same institution over time have not been described. We sought to define the association between EV-D68 loads and sequence variation, and the clinical characteristic in hospitalized children at our institution from 2011 to 2014. Methods May through November 2014, and August to September 2011 to 2013, a convenience sample of nasopharyngeal specimens from children with rhinovirus (RV)/EV respiratory infections were tested for EV-D68 by RT-PCR. Clinical data were compared between children with RV/EV-non-EV-D68 and EV-D68 infections, and among children with EV-D68 infections categorized as healthy, asthmatics, and chronic medical conditions. EV-D68 loads were analyzed in relation to disease severity parameters and sequence variability characterized over time. Results In 2014, 44% (192/438) of samples tested positive for EV-D68 vs. 10% (13/130) in 2011–13 (p<0.0001). PICU admissions (p<0.0001) and non-invasive ventilation (p<0.0001) were more common in children with EV-D68 vs. RV/EV-non-EV-D68 infections. Asthmatic EV-D68+ children, required supplemental oxygen administration (p = 0.03) and PICU admissions (p <0.001) more frequently than healthy children or those with chronic medical conditions; however oxygen duration (p<0.0001), and both PICU and total hospital stay (p<0.01) were greater in children with underlying medical conditions, irrespective of viral burden. By phylogenetic analysis, the 2014 EV-D68 strains clustered into a new sublineage within clade B. Conclusions This is one of the largest pediatric cohorts described from the EV-D68 outbreak. Irrespective of viral loads, EV-D68 was associated with high morbidity in children with asthma and co-morbidities. While EV-D68 circulated before 2014, the outbreak isolates clustered differently than those from prior years.
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Affiliation(s)
- Katherine Moyer
- Department of Pediatrics, Division of Infectious Diseases, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Huanyu Wang
- Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Douglas Salamon
- Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Amy Leber
- Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- * E-mail: (AM); (AL)
| | - Asuncion Mejias
- Department of Pediatrics, Division of Infectious Diseases, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail: (AM); (AL)
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28
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Patel MC, Wang W, Pletneva LM, Rajagopala SV, Tan Y, Hartert TV, Boukhvalova MS, Vogel SN, Das SR, Blanco JCG. Enterovirus D-68 Infection, Prophylaxis, and Vaccination in a Novel Permissive Animal Model, the Cotton Rat (Sigmodon hispidus). PLoS One 2016; 11:e0166336. [PMID: 27814404 PMCID: PMC5096705 DOI: 10.1371/journal.pone.0166336] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 10/26/2016] [Indexed: 12/17/2022] Open
Abstract
In recent years, there has been a significant increase in detection of Enterovirus D-68 (EV-D68) among patients with severe respiratory infections worldwide. EV-D68 is now recognized as a re-emerging pathogen; however, due to lack of a permissive animal model for EV-D68, a comprehensive understanding of the pathogenesis and immune response against EV-D68 has been hampered. Recently, it was shown that EV-D68 has a strong affinity for α2,6-linked sialic acids (SAs) and we have shown previously that α2,6-linked SAs are abundantly present in the respiratory tract of cotton rats (Sigmodon hispidus). Thus, we hypothesized that cotton rats could be a potential model for EV-D68 infection. Here, we evaluated the ability of two recently isolated EV-D68 strains (VANBT/1 and MO/14/49), along with the historical prototype Fermon strain (ATCC), to infect cotton rats. We found that cotton rats are permissive to EV-D68 infection without virus adaptation. The different strains of EV-D68 showed variable infection profiles and the ability to produce neutralizing antibody (NA) upon intranasal infection or intramuscular immunization. Infection with the VANBT/1 resulted in significant induction of pulmonary cytokine gene expression and lung pathology. Intramuscular immunization with live VANBT/1 or MO/14/49 induced strong homologous antibody responses, but a moderate heterologous NA response. We showed that passive prophylactic administration of serum with high content of NA against VANBT/1 resulted in an efficient antiviral therapy. VANBT/1-immunized animals showed complete protection from VANBT/1 challenge, but induced strong pulmonary Th1 and Th2 cytokine responses and enhanced lung pathology, indicating the generation of exacerbated immune response by immunization. In conclusion, our data illustrate that the cotton rat is a powerful animal model that provides an experimental platform to investigate pathogenesis, immune response, anti-viral therapies and vaccines against EV-D68 infection.
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Affiliation(s)
- Mira C. Patel
- Sigmovir Biosystems Inc., Rockville, Maryland, United States of America
- Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, United States of America
| | - Wei Wang
- Infectious Diseases Group, J. Craig Venter Institute, Rockville, Maryland, United States of America
| | | | - Seesandra V. Rajagopala
- Infectious Diseases Group, J. Craig Venter Institute, Rockville, Maryland, United States of America
| | - Yi Tan
- Infectious Diseases Group, J. Craig Venter Institute, Rockville, Maryland, United States of America
| | - Tina V. Hartert
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | | | - Stefanie N. Vogel
- Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, United States of America
| | - Suman R. Das
- Infectious Diseases Group, J. Craig Venter Institute, Rockville, Maryland, United States of America
- * E-mail: (JCGB); (SRD)
| | - Jorge C. G. Blanco
- Sigmovir Biosystems Inc., Rockville, Maryland, United States of America
- * E-mail: (JCGB); (SRD)
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Thongpan I, Wanlapakorn N, Vongpunsawad S, Linsuwanon P, Theamboonlers A, Payungporn S, Poovorawan Y. Prevalence and Phylogenetic Characterization of Enterovirus D68 in Pediatric Patients with Acute Respiratory Tract Infection in Thailand. Jpn J Infect Dis 2016; 69:426-430. [PMID: 26567839 DOI: 10.7883/yoken.jjid.2015.352] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Enterovirus D68 (EV-D68) is associated with severe lower respiratory tract infection and neurological abnormalities including acute myelitis and cranial nerve dysfunction. To determine whether an increased incidence of EV-D68 occurs in Southeast Asia, we retrospectively tested specimens collected from Thai pediatric patients who were less than 5 years of age and presented with acute respiratory tract infections between 2012 and 2014. Reverse transcription-polymerase chain reaction and nucleotide sequencing of the 5'-UTR/VP2 region were used to identify EV-D68. We also examined the epidemiological pattern of EV-D68 since 2009, when it was first identified in Thailand, and compiled records of clinical manifestations in children with confirmed EV-D68 infection. From 837 samples, 5 samples (0.6%) tested positive for EV-D68. All patients presented with viral pneumonia and required hospitalization. Phylogenetic analysis of the VP4/VP2 regions revealed that EV-D68 strains circulating in Thailand between 2012 and 2014 were closely related to strains reported in Japan, United Kingdom, China, and France. Continued surveillance of probable EV-D68-associated severe respiratory tract infection and the development of a rapid diagnostic test for EV-D68 are essential in supporting awareness and facilitating disease prevention and control.
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Affiliation(s)
- Ilada Thongpan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University
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Zhang T, Li A, Chen M, Wu J, Huang F. Respiratory infections associated with enterovirus D68 from 2011 to 2015 in Beijing, China. J Med Virol 2016; 88:1529-34. [PMID: 26896830 PMCID: PMC7166988 DOI: 10.1002/jmv.24505] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2016] [Indexed: 11/24/2022]
Abstract
Enterovirus D68 (EV-D68) is an emergent viral pathogen associated with mild to severe respiratory infections. In this study, we describe respiratory infections associated with EV-D68 in Beijing over a 4 year period. Total nucleic acid was extracted from 7,945 clinical specimens collected between January 5, 2011 and July 30, 2015 in Beijing and used for detecting EV-D68 and other enteroviruses by real-time PCR. Overall, 555/7,945 (6.99%) specimens were enterovirus positive: 12/7,945 (0.2%) specimens were EV-D68 positive. Of these patients, 11 were pediatric patients and 1 was a 76-year-old man. The main symptoms for the 12 EV-D68 positive patients were fever (10/12, 83.3%) and cough (6/12, 50%). Ten EV-D68 infection cases were identified in autumn or winter season. The phylogenetic relationships of the 12 EV-D68 viral strains with other strains were analyzed based on the sequences of viral protein 1(VP1). The EV-D68 strains from 2011 to 2013 belonged to groups 1 or 3, while all strains in 2014 were clustered into group 1 together with the strains circulating in the USA. In conclusion, EV-D68 played a role in respiratory infections in Beijing during this period. In addition, the most common EV-D68 strain detected was similar to that circulating in the USA in 2014. J. Med. Virol. 88:1529-1534, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Tiegang Zhang
- Beijing Center for Disease Prevention and ControlBeijingP. R. China
| | - Aihua Li
- Beijing Center for Disease Prevention and ControlBeijingP. R. China
| | - Meng Chen
- Beijing Center for Disease Prevention and ControlBeijingP. R. China
| | - Jiang Wu
- Beijing Center for Disease Prevention and ControlBeijingP. R. China
| | - Fang Huang
- Beijing Center for Disease Prevention and ControlBeijingP. R. China
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Abstract
Enterovirus D68 (EV-D68) is a member of the species Enterovirus D in the genus Enterovirus of the Picornaviridae family. EV-D68 was first isolated in the United States in 1962 and is primarily an agent of respiratory disease. Infections with EV-D68 have been rarely reported until recently, when reports of EV-D68 associated with respiratory disease increased notably worldwide. An outbreak in 2014 in the United States, for example, involved more than 1,000 cases of severe respiratory disease that occurred across almost all states. Phylogenetic analysis of all EV-D68 sequences indicates that the circulating strains of EV-D68 can be classified into two lineages, lineage 1 and lineage 2. In contrast to the prototype Fermon strain, all circulating strains have deletions in their genomes. Respiratory illness associated with EV-D68 infection ranges from mild illness that just needs outpatient service to severe illness requiring intensive care and mechanical ventilation. To date, there are no specific medicines and vaccines to treat or prevent EV-D68 infection. This review provides a detailed overview about our current understanding of EV-D68-related virology, epidemiology and clinical syndromes, pathogenesis, and laboratory diagnostics.
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Affiliation(s)
- Zichun Xiang
- MOH Key Laboratory of Systems Biology of Pathogens, and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, P.R. China
| | - Jianwei Wang
- MOH Key Laboratory of Systems Biology of Pathogens, and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, P.R. China
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Gong YN, Yang SL, Shih SR, Huang YC, Chang PY, Huang CG, Kao KC, Hu HC, Liu YC, Tsao KC. Molecular evolution and the global reemergence of enterovirus D68 by genome-wide analysis. Medicine (Baltimore) 2016; 95:e4416. [PMID: 27495059 PMCID: PMC4979813 DOI: 10.1097/md.0000000000004416] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Human enterovirus D68 (EV-D68) was first reported in the United States in 1962; thereafter, a few cases were reported from 1970 to 2005, but 2 outbreaks occurred in the Philippines (2008) and the United States (2014). However, little is known regarding the molecular evolution of this globally reemerging virus due to a lack of whole-genome sequences and analyses. Here, all publically available sequences including 147 full and 1248 partial genomes from GenBank were collected and compared at the clade and subclade level; 11 whole genomes isolated in Taiwan (TW) in 2014 were also added to the database. Phylogenetic trees were constructed to identify a new subclade, B3, and represent clade circulations among strains. Nucleotide sequence identities of the VP1 gene were 94% to 95% based on a comparison of subclade B3 to B1 and B2 and 87% to 91% when comparing A, C, and D. The patterns of clade circulation need to be clarified to improve global monitoring of EV-D68, even though this virus showed lower diversity among clades compared with the common enterovirus EV-71. Notably, severe cases isolated from Taiwan and China in 2014 were found in subclade B3. One severe case from Taiwan occurred in a female patient with underlying angioimmunoblastic T-cell lymphoma, from whom a bronchoalveolar lavage specimen was obtained. Although host factors play a key role in disease severity, we cannot exclude the possibility that EV-D68 may trigger clinical symptoms or death. To further investigate the genetic diversity of EV-D68, we reported 34 amino acid (aa) polymorphisms identified by comparing subclade B3 to B1 and B2. Clade D strains had a 1-aa deletion and a 2-aa insertion in the VP1 gene, and 1 of our TW/2014 strains had a shorter deletion in the 5' untranslated region than a previously reported deletion. In summary, a new subclade, genetic indels, and polymorphisms in global strains were discovered elucidating evolutionary and epidemiological trends of EV-D68, and 11 genomes were added to the database. Virus variants may contribute to disease severity and clinical manifestations, and further studies are needed to investigate the associations between genetic diversity and clinical outcomes.
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Affiliation(s)
- Yu-Nong Gong
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital
| | - Shu-Li Yang
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital
- Department of Medical Biotechnology and Laboratory Science
| | - Shin-Ru Shih
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital
- Department of Medical Biotechnology and Laboratory Science
- Research Center for Emerging Viral Infections, Chang Gung University
| | - Yhu-Chering Huang
- Department of Pediatrics, Linkou Chang Gung Memorial Hospital
- College of Medicine, Chang Gung University
| | - Pi-Yueh Chang
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital
- Department of Medical Biotechnology and Laboratory Science
| | - Chung-Guei Huang
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital
- Department of Medical Biotechnology and Laboratory Science
- Research Center for Emerging Viral Infections, Chang Gung University
| | - Kuo-Chin Kao
- Department of Respiratory Therapy
- Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital
- Department of Respiratory Therapy
- Department of Pulmonary and Critical Care Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Han-Chung Hu
- Department of Respiratory Therapy
- Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital
- Department of Respiratory Therapy
- Department of Pulmonary and Critical Care Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Chun Liu
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital
| | - Kuo-Chien Tsao
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital
- Department of Medical Biotechnology and Laboratory Science
- Research Center for Emerging Viral Infections, Chang Gung University
- Correspondence: Kuo-ChienTsao, Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan (e-mail: )
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Böttcher S, Prifert C, Weißbrich B, Adams O, Aldabbagh S, Eis-Hübinger AM, Diedrich S. Detection of enterovirus D68 in patients hospitalised in three tertiary university hospitals in Germany, 2013 to 2014. Euro Surveill 2016; 21:30227. [DOI: 10.2807/1560-7917.es.2016.21.19.30227] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 03/09/2016] [Indexed: 12/25/2022] Open
Abstract
Enterovirus D68 (EV-D68) has been recognised as a worldwide emerging pathogen associated with severe respiratory symptoms since 2009. We here report EV-D68 detection in hospitalised patients with acute respiratory infection admitted to three tertiary hospitals in Germany between January 2013 and December 2014. From a total of 14,838 respiratory samples obtained during the study period, 246 (1.7%) tested enterovirus-positive and, among these, 39 (15.9%) were identified as EV-D68. Infection was observed in children and teenagers (0–19 years; n=31), the majority (n=22) being under five years-old, as well as in adults > 50 years of age (n=8). No significant difference in prevalence was observed between the 2013 and 2014 seasons. Phylogenetic analyses based on viral protein 1 (VP1) sequences showed co-circulation of different EV-D68 lineages in Germany. Sequence data encompassing the entire capsid region of the genome were analysed to gain information on amino acid changes possibly relevant for immunogenicity and revealed mutations in two recently described pleconaril binding sites.
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Affiliation(s)
- Sindy Böttcher
- National Reference Centre for Poliomyelitis and Enteroviruses, Robert Koch-Institute, Germany
| | - Christiane Prifert
- Institute of Virology and Immunobiology, University of Würzburg, Germany
| | - Benedikt Weißbrich
- Institute of Virology and Immunobiology, University of Würzburg, Germany
| | - Ortwin Adams
- Institute of Virology, University Hospital of Düsseldorf, Germany
| | | | | | - Sabine Diedrich
- National Reference Centre for Poliomyelitis and Enteroviruses, Robert Koch-Institute, Germany
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Abstract
ABSTRACT
Enterovirus-D68 (EV-D68) is a unique enterovirus, similar to human rhinoviruses, spread via the respiratory route and primarily causing respiratory disease. Increasing clusters of EV-D68 associated respiratory disease have been reported since 2008, with the largest reported outbreak occurring in North America in 2014. Epidemiologic data and biological plausibility support an association of EV-D68 with the neurologic condition, acute flaccid myelitis. Diagnosis requires EV-D68 specific PCR or viral sequencing of respiratory specimens. Treatment consists of supportive care, as there are no currently available effective vaccines or antiviral therapies. Further research is needed to prepare for future EV-D68 outbreaks of respiratory or neurologic disease.
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Matsumoto M, Awano H, Ogi M, Tomioka K, Unzaki A, Nishiyama M, Toyoshima D, Taniguchi-Ikeda M, Ishida A, Nagase H, Morioka I, Iijima K. A pediatric patient with interstitial pneumonia due to enterovirus D68. J Infect Chemother 2016; 22:712-5. [PMID: 27118532 DOI: 10.1016/j.jiac.2016.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 03/10/2016] [Accepted: 03/12/2016] [Indexed: 11/18/2022]
Abstract
Enterovirus D68 (EV-D68) infection is associated with upper and lower respiratory tract symptoms such as fever, cough, and wheezing. Pediatric patients with EV-D68 infection easily develop more severe respiratory complications compared to patients infected with other species of enterovirus, and consequently, have a higher rate of hospitalization and admission to intensive care units. Therefore, the clinical picture of respiratory complications associated with EV-D68 infection needs to be elucidated. Here, we report a 4-year-old girl of EV-D68 infection that required artificial respiration management within 24 h from the onset of cold symptoms. The patient was diagnosed with interstitial pneumonia on the basis of chest imaging findings with patchy, funicular and frosted glassy shadows, increased blood markers of surfactant protein-A, surfactant protein-D and sialylated carbohydrate antigen KL-6, and increased neutrophils and lymphocytes in the bronchoalveolar lavage. Steroids showed a remarkable effect in her treatment. Further investigations are needed to confirm the efficacy of steroids for interstitial pneumonia due to EV-D68 infection. As rapid deterioration of respiratory status is observed in EV-D68 infection, the possibility of interstitial pneumonia may be considered.
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MESH Headings
- Biomarkers/blood
- Bronchoalveolar Lavage Fluid/cytology
- Bronchoalveolar Lavage Fluid/microbiology
- C-Reactive Protein/analysis
- Child, Preschool
- Enterovirus D, Human/isolation & purification
- Enterovirus Infections/blood
- Enterovirus Infections/diagnostic imaging
- Enterovirus Infections/drug therapy
- Enterovirus Infections/virology
- Female
- Glucocorticoids/therapeutic use
- Hospitalization
- Humans
- Lung Diseases, Interstitial/blood
- Lung Diseases, Interstitial/diagnostic imaging
- Lung Diseases, Interstitial/drug therapy
- Lung Diseases, Interstitial/virology
- Methylprednisolone/therapeutic use
- Mucin-1/blood
- Pneumonia, Viral/blood
- Pneumonia, Viral/diagnostic imaging
- Pneumonia, Viral/drug therapy
- Pneumonia, Viral/virology
- Polymerase Chain Reaction
- Pulmonary Surfactant-Associated Protein A/blood
- Pulmonary Surfactant-Associated Protein D/blood
- Respiration, Artificial
- Tomography, X-Ray Computed
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Affiliation(s)
- Masaaki Matsumoto
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroyuki Awano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Miki Ogi
- Infectious Disease Research Division, Hyogo Prefectural Institute of Public Health and Consumer Sciences, Kobe, Japan
| | - Kazumi Tomioka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ai Unzaki
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masahiro Nishiyama
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Daisaku Toyoshima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | | | - Akihito Ishida
- Kobe Children's Primary Emergency Medical Center, Kobe, Japan
| | - Hiroaki Nagase
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ichiro Morioka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
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Holm-Hansen CC, Midgley SE, Fischer TK. Global emergence of enterovirus D68: a systematic review. THE LANCET. INFECTIOUS DISEASES 2016; 16:e64-e75. [PMID: 26929196 DOI: 10.1016/s1473-3099(15)00543-5] [Citation(s) in RCA: 253] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 12/09/2015] [Accepted: 12/15/2015] [Indexed: 01/15/2023]
Abstract
Since its discovery in California in 1962, reports of enterovirus D68 have been infrequent. Before 2014, infections were confirmed in only 699 people worldwide. In August, 2014, two paediatric hospitals in the USA reported increases in the number of patients with severe respiratory illness, with an over-representation in children with asthma. Shortly after, the authorities recognised a nationwide outbreak, which then spread to Canada, Europe, and Asia. In 2014, more than 2000 cases of enterovirus D68 were reported in 20 countries. Concurrently, clusters of children with acute flaccid paralysis of unknown cause were reported in several US states and in Europe. Enterovirus D68 infection was confirmed in some of the paralysed children, but not all. Complications in patients who were severely neurologically affected resemble those caused by poliomyelitis. In this paper we systematically review reports on enterovirus D68 to estimate its global epidemiology and its ability to cause respiratory infections and neurological damage in children. We extracted data from 70 papers to report on prevalence, symptoms, hospitalisation and mortality, and complications of enterovirus D68, both before and during the large outbreak of 2014. The magnitude and severity of the enterovirus D68 outbreak underscores a need for improved diagnostic work-up of paediatric respiratory illness, not only to prevent unnecessary use of antibiotics, but also to ensure better surveillance of diseases. Existing surveillance systems should be assessed in terms of capacity and ability to detect and report any upsurge of respiratory viruses such as enterovirus D68 in a timely manner, and focus should be paid to development of preventive measures against these emerging enteroviruses that have potential for severe disease.
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Affiliation(s)
- Charlotte Carina Holm-Hansen
- Virology Surveillance and Research Section, Department of Microbiological Diagnostics and Virology, Statens Serum Institut, Copenhagen, Denmark
| | - Sofie Elisabeth Midgley
- Virology Surveillance and Research Section, Department of Microbiological Diagnostics and Virology, Statens Serum Institut, Copenhagen, Denmark
| | - Thea Kølsen Fischer
- Virology Surveillance and Research Section, Department of Microbiological Diagnostics and Virology, Statens Serum Institut, Copenhagen, Denmark; Center for Global Health and Department of Infectious Diseases, Clinical Institute, University of Southern Denmark, Odense, Denmark.
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37
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Abstract
PURPOSE OF REVIEW There are over 100 serotypes of human enteroviruses, which cause a spectrum of illnesses, including meningitis, encephalitis, paralysis, myocarditis and rash. Increasing incidence of hand-foot-and-mouth disease in the Asia-Pacific region and recent outbreaks of enterovirus-associated disease, such as severe respiratory illness in the United States in 2014, highlight the threat of these viruses to human health. RECENT FINDINGS We describe recent outbreaks of human enteroviruses and summarize knowledge gaps regarding their burden, spectrum of diseases and epidemiology. SUMMARY Reported outbreaks of respiratory, neurological, skin and eye diseases associated with human enteroviruses have increased in frequency and size in recent years. Improved molecular diagnostics and genetic sequence analysis are beginning to reveal the complex dynamics of individual serotypes and genotypes, and their contribution to these outbreaks. However, the biological mechanisms underlying their emergence and transmission dynamics remain elusive. They are likely to involve changes in the virus, such as fitness, antigenicity, virulence or tropism, and in the human population, such as levels of sanitation and of homotypic and heterotypic immunity. Improvements in surveillance, serological surveys and detailed genetic and antigenic characterization of viral populations would help to elucidate these mechanisms. This will be important for the design of outbreak control and vaccine development strategies.
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38
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Xiang Z, Liu L, Lei X, Zhou Z, He B, Wang J. 3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7. J Virol 2016; 90:1613-21. [PMID: 26608321 PMCID: PMC4719596 DOI: 10.1128/jvi.02395-15] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 11/18/2015] [Indexed: 12/16/2022] Open
Abstract
UNLABELLED Human enterovirus 68 (EV-D68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family. Over the past several years, clusters of EV-D68 infections have occurred worldwide. A recent outbreak in the United States is the largest one associated with severe respiratory illness and neurological complication. Although clinical symptoms are recognized, the virus remains poorly understood. Here we report that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7), an immune factor with a pivotal role in viral pathogenesis. This process depends on 3C(pro), an EV-D68-encoded protease, to mediate IRF7 cleavage. When expressed in host cells, 3C(pro) targets Q167 and Q189 within the constitutive activation domain, resulting in cleavage of IRF7. Accordingly, wild-type IRF7 is fully active. However, IRF7 cleavage abrogated its capacity to activate type I interferon expression and limit replication of EV-D68. Notably, IRF7 cleavage strictly requires the protease activity of 3C(pro). Together, these results suggest that a dynamic interplay between 3C(pro) and IRF7 may determine the outcome of EV-D68 infection. IMPORTANCE EV-D68 is a globally emerging pathogen, but the molecular basis of EV-D68 pathogenesis is unclear. Here we report that EV-D68 inhibits innate immune responses by targeting an immune factor, IRF7. This involves the 3C protease encoded by EV-D68, which mediates the cleavage of IRF7. These observations suggest that the 3C(pro)-IRF7 interaction may represent an interface that dictates EV-D68 infection.
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Affiliation(s)
- Zichun Xiang
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China
| | - Lulu Liu
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China
| | - Xiaobo Lei
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China
| | - Zhuo Zhou
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China
| | - Bin He
- Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois, USA
| | - Jianwei Wang
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China
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39
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Royston L, Tapparel C. Rhinoviruses and Respiratory Enteroviruses: Not as Simple as ABC. Viruses 2016; 8:E16. [PMID: 26761027 PMCID: PMC4728576 DOI: 10.3390/v8010016] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 12/09/2015] [Accepted: 12/28/2015] [Indexed: 12/21/2022] Open
Abstract
Rhinoviruses (RVs) and respiratory enteroviruses (EVs) are leading causes of upper respiratory tract infections and among the most frequent infectious agents in humans worldwide. Both are classified in the Enterovirus genus within the Picornaviridae family and they have been assigned to seven distinct species, RV-A, B, C and EV-A, B, C, D. As viral infections of public health significance, they represent an important financial burden on health systems worldwide. However, the lack of efficient antiviral treatment or vaccines against these highly prevalent pathogens prevents an effective management of RV-related diseases. Current advances in molecular diagnostic techniques have revealed the presence of RV in the lower respiratory tract and its role in lower airway diseases is increasingly reported. In addition to an established etiological role in the common cold, these viruses demonstrate an unexpected capacity to spread to other body sites under certain conditions. Some of these viruses have received particular attention recently, such as EV-D68 that caused a large outbreak of respiratory illness in 2014, respiratory EVs from species C, or viruses within the newly-discovered RV-C species. This review provides an update of the latest findings on clinical and fundamental aspects of RV and respiratory EV, including a summary of basic knowledge of their biology.
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Affiliation(s)
- Léna Royston
- University of Geneva Faculty of Medicine, 1 Rue Michel-Servet, 1205 Geneva, Switzerland.
- Laboratory of Virology, Division of Infectious Diseases, University of Geneva Hospitals, 4 Rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerland.
| | - Caroline Tapparel
- University of Geneva Faculty of Medicine, 1 Rue Michel-Servet, 1205 Geneva, Switzerland.
- Laboratory of Virology, Division of Infectious Diseases, University of Geneva Hospitals, 4 Rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerland.
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40
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Pabbaraju K, Wong S, Drews SJ, Tipples G, Tellier R. Full genome analysis of enterovirus D-68 strains circulating in Alberta, Canada. J Med Virol 2015; 88:1194-203. [PMID: 26643129 DOI: 10.1002/jmv.24444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2015] [Indexed: 11/09/2022]
Abstract
A widespread outbreak of enterovirus (EV)-D68 that started in the summer of 2014 has been reported in the USA and Canada. During the course of this outbreak, EV-D68 was identified as a possible cause of acute, unexplained severe respiratory illness and a temporal association was observed between acute flaccid paralysis with anterior myelitis and EV-D68 detection in the upper respiratory tract. In this study, four nasopharyngeal samples collected from patients in Alberta, Canada with a laboratory diagnosis of EV-D68 were used to determine the near full-length genome sequence directly from the specimens. Phylogenetic analysis was performed to study the genotypes and pathogenesis of the circulating strains. Our results support the contention that mutations in the VP1 gene and other regions of the genome causing altered antigenicity, as well as lack of immunity in the younger population, may be responsible for the increased severe respiratory disease outbreaks of EV-D68 worldwide.
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Affiliation(s)
- Kanti Pabbaraju
- Provincial Laboratory for Public Health, Calgary, Alberta, Canada
| | - Sallene Wong
- Provincial Laboratory for Public Health, Calgary, Alberta, Canada
| | - Steven J Drews
- Provincial Laboratory for Public Health, Edmonton, Alberta, Canada.,Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Graham Tipples
- Provincial Laboratory for Public Health, Edmonton, Alberta, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Raymond Tellier
- Provincial Laboratory for Public Health, Calgary, Alberta, Canada.,Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Alberta, Canada
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41
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Molecular Evolution and Intraclade Recombination of Enterovirus D68 during the 2014 Outbreak in the United States. J Virol 2015; 90:1997-2007. [PMID: 26656685 DOI: 10.1128/jvi.02418-15] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 11/30/2015] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED In August 2014, an outbreak of enterovirus D68 (EV-D68) occurred in North America, causing severe respiratory disease in children. Due to a lack of complete genome sequence data, there is only a limited understanding of the molecular evolution and epidemiology of EV-D68 during this outbreak, and it is uncertain whether the differing clinical manifestations of EV-D68 infection are associated with specific viral lineages. We developed a high-throughput complete genome sequencing pipeline for EV-D68 that produced a total of 59 complete genomes from respiratory samples with a 95% success rate, including 57 genomes from Kansas City, MO, collected during the 2014 outbreak. With these data in hand, we performed phylogenetic analyses of complete genome and VP1 capsid protein sequences. Notably, we observed considerable genetic diversity among EV-D68 isolates in Kansas City, manifest as phylogenetically distinct lineages, indicative of multiple introductions of this virus into the city. In addition, we identified an intersubclade recombination event within EV-D68, the first recombinant in this virus reported to date. Finally, we found no significant association between EV-D68 genetic variation, either lineages or individual mutations, and a variety of demographic and clinical variables, suggesting that host factors likely play a major role in determining disease severity. Overall, our study revealed the complex pattern of viral evolution within a single geographic locality during a single outbreak, which has implications for the design of effective intervention and prevention strategies. IMPORTANCE Until recently, EV-D68 was considered to be an uncommon human pathogen, associated with mild respiratory illness. However, in 2014 EV-D68 was responsible for more than 1,000 disease cases in North America, including severe respiratory illness in children and acute flaccid myelitis, raising concerns about its potential impact on public health. Despite the emergence of EV-D68, a lack of full-length genome sequences means that little is known about the molecular evolution of this virus within a single geographic locality during a single outbreak. Here, we doubled the number of publicly available complete genome sequences of EV-D68 by performing high-throughput next-generation sequencing, characterized the evolutionary history of this outbreak in detail, identified a recombination event, and investigated whether there was any correlation between the demographic and clinical characteristics of the patients and the viral variant that infected them. Overall, these results will help inform the design of intervention strategies for EV-D68.
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42
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Du J, Zheng B, Zheng W, Li P, Kang J, Hou J, Markham R, Zhao K, Yu XF. Analysis of Enterovirus 68 Strains from the 2014 North American Outbreak Reveals a New Clade, Indicating Viral Evolution. PLoS One 2015; 10:e0144208. [PMID: 26630383 PMCID: PMC4667938 DOI: 10.1371/journal.pone.0144208] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 11/13/2015] [Indexed: 12/14/2022] Open
Abstract
Enterovirus 68 (EVD68) causes respiratory illness, mostly in children. Despite a reported low-level of transmission, the occurrence of several recent outbreaks worldwide including the 2014 outbreak in North America has raised concerns regarding the pathogenesis and evolution of EVD68. To elucidate the phylogenetic features of EVD68 and possible causes for the 2014 outbreak, 216 EVD68 strain sequences were retrieved from Genbank, including 22 from the 2014 outbreak. Several geographic and genotypic origins were established for these 22 strains, 19 of which were classified as Clade B. Of these 19 strains, 17 exhibited subsequent clustering and variation in protein residues involved in host-receptor interaction and/or viral antigenicity. Approximately 18 inter-clade variations were detected in VP1, which led to the identification of a new Clade D in EVD68 strains. The classification of this new clade was also verified by the re-construction of a Neighbor-Joining tree during the phylogenetic analysis. In addition, our results indicate that members of Clade B containing highly specific alterations in VP1 protein residues were the foremost contributors to the 2014 outbreak in the US. Altered host-receptor interaction and/or host immune recognition may explain the evolution of EVD68 as well as the global emergence and ongoing adaptation of this virus.
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Affiliation(s)
- Juan Du
- Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Baisong Zheng
- Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Wenwen Zheng
- Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Peng Li
- Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Jian Kang
- Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Jingwei Hou
- Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Richard Markham
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Ke Zhao
- Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China
- * E-mail: (KZ); (XFY)
| | - Xiao-Fang Yu
- Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
- * E-mail: (KZ); (XFY)
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43
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Messacar K, Abzug MJ, Dominguez SR. 2014 outbreak of enterovirus D68 in North America. J Med Virol 2015; 88:739-45. [PMID: 26489019 DOI: 10.1002/jmv.24410] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2015] [Indexed: 11/07/2022]
Abstract
Enterovirus D68 (EV-D68) is an emerging picornavirus which causes severe respiratory disease, predominantly in children. In 2014, the largest and most widespread outbreak of EV-D68 described to date was reported in North America. Hospitals throughout the United States and Canada reported surges in patient volumes and resource utilization from August to October, 2014. In the US a total of 1,153 infections were confirmed in 49 states, although this is an underestimate of the likely millions of cases that occurred but were not tested. EV-D68 was detected in 14 patients who died; the role of the virus in these deaths is unknown. A possible association between EV-D68 and cases of acute flaccid paralysis with spinal cord gray matter lesions, known as acute flaccid myelitis, was observed during the outbreak and is under investigation. The 2014 outbreak of EV-D68 in North America demonstrates the public health importance of this emerging pathogen.
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Affiliation(s)
- Kevin Messacar
- Pediatric Hospital Medicine and Infectious Diseases, University of Colorado/Children's Hospital Colorado, Aurora, Colorado
| | - Mark J Abzug
- Pediatric Infectious Diseases, University of Colorado/Children's Hospital Colorado, Aurora, Colorado
| | - Samuel R Dominguez
- Pediatric Infectious Diseases, University of Colorado/Children's Hospital Colorado, Aurora, Colorado
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44
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Abstract
The outbreak of Enterovirus D-68 (EV-D68) in the United States in 2014 raised great interest due to it affecting large numbers of people and because patients presented with severe respiratory and/or central nervous system involvement. Many studies have tried to evaluate the biologic and genetic characteristics of this virus, its association with disease development and the possibility of infection prevention and therapy. The main aim of this paper is to discuss what is presently known and what might be expected in the future regarding EV-D68. We highlight that further studies are needed to precisely define the epidemiology and total burden of EV-D68, the real age prevalence, and the factors that may lead to negative outcomes in some patients and not in others. Moreover, if recently reported clinical data are confirmed, specific efficacious prophylactic and therapeutic measures should be urgently developed.
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Affiliation(s)
- Nicola Principi
- a Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation , Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
| | - Susanna Esposito
- a Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation , Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
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45
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Midgley CM, Watson JT, Nix WA, Curns AT, Rogers SL, Brown BA, Conover C, Dominguez SR, Feikin DR, Gray S, Hassan F, Hoferka S, Jackson MA, Johnson D, Leshem E, Miller L, Nichols JB, Nyquist AC, Obringer E, Patel A, Patel M, Rha B, Schneider E, Schuster JE, Selvarangan R, Seward JF, Turabelidze G, Oberste MS, Pallansch MA, Gerber SI. Severe respiratory illness associated with a nationwide outbreak of enterovirus D68 in the USA (2014): a descriptive epidemiological investigation. THE LANCET RESPIRATORY MEDICINE 2015; 3:879-87. [PMID: 26482320 PMCID: PMC5693332 DOI: 10.1016/s2213-2600(15)00335-5] [Citation(s) in RCA: 178] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 08/14/2015] [Accepted: 08/17/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND Enterovirus D68 (EV-D68) has been infrequently reported historically, and is typically associated with isolated cases or small clusters of respiratory illness. Beginning in August, 2014, increases in severe respiratory illness associated with EV-D68 were reported across the USA. We aimed to describe the clinical, epidemiological, and laboratory features of this outbreak, and to better understand the role of EV-D68 in severe respiratory illness. METHODS We collected regional syndromic surveillance data for epidemiological weeks 23 to 44, 2014, (June 1 to Nov 1, 2014) and hospital admissions data for epidemiological weeks 27 to 44, 2014, (June 29 to Nov 1, 2014) from three states: Missouri, Illinois and Colorado. Data were also collected for the same time period of 2013 and 2012. Respiratory specimens from severely ill patients nationwide, who were rhinovirus-positive or enterovirus-positive in hospital testing, were submitted between Aug 1, and Oct 31, 2014, and typed by molecular sequencing. We collected basic clinical and epidemiological characteristics of EV-D68 cases with a standard data collection form submitted with each specimen. We compared patients requiring intensive care with those who did not, and patients requiring ventilator support with those who did not. Mantel-Haenszel χ(2) tests were used to test for statistical significance. FINDINGS Regional and hospital-level data from Missouri, Illinois, and Colorado showed increases in respiratory illness between August and September, 2014, compared with in 2013 and 2012. Nationwide, 699 (46%) of 1529 patients tested were confirmed as EV-D68. Among the 614 EV-D68-positive patients admitted to hospital, age ranged from 3 days to 92 years (median 5 years). Common symptoms included dyspnoea (n=513 [84%]), cough (n=500 [81%]), and wheezing (n=427 [70%]); 294 (48%) patients had fever. 338 [59%] of 574 were admitted to intensive care units, and 145 (28%) of 511 received ventilator support; 322 (52%) of 614 had a history of asthma or reactive airway disease; 200 (66%) of 304 patients with a history of asthma or reactive airway disease required intensive care compared with 138 (51%) of 270 with no history of asthma or reactive airway disease (p=0·0004). Similarly, 89 (32%) of 276 patients with a history of asthma or reactive airway disease required ventilator support compared with 56 (24%) of 235 patients with no history of asthma or reactive airway disease (p=0·039). INTERPRETATION In 2014, EV-D68 caused widespread severe respiratory illness across the USA, disproportionately affecting those with asthma. This unexpected event underscores the need for robust surveillance of enterovirus types, enabling improved understanding of virus circulation and disease burden. FUNDING None.
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Affiliation(s)
- Claire M Midgley
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA; Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, GA, USA.
| | - John T Watson
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - W Allan Nix
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Aaron T Curns
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Shannon L Rogers
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Betty A Brown
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Craig Conover
- Illinois Department of Public Health, Chicago, IL, USA
| | | | - Daniel R Feikin
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Samantha Gray
- Cook County Department of Public Health, Oak Forest, IL, USA
| | - Ferdaus Hassan
- Children's Mercy Hospitals and Clinics, Kansas City, MO, USA
| | | | | | - Daniel Johnson
- The University of Chicago Comer Children's Hospital, Chicago, IL, USA
| | - Eyal Leshem
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Lisa Miller
- Colorado Department of Public Health and Environment, Denver, CO, USA
| | | | | | - Emily Obringer
- The University of Chicago Comer Children's Hospital, Chicago, IL, USA
| | - Ajanta Patel
- The University of Chicago Comer Children's Hospital, Chicago, IL, USA
| | - Megan Patel
- Cook County Department of Public Health, Oak Forest, IL, USA
| | - Brian Rha
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Eileen Schneider
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | | | | | - Jane F Seward
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - George Turabelidze
- Missouri Department of Health and Senior Services, Jefferson City, MO, USA
| | - M Steven Oberste
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Mark A Pallansch
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Susan I Gerber
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
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Poelman R, Schuffenecker I, Van Leer-Buter C, Josset L, Niesters HGM, Lina B. European surveillance for enterovirus D68 during the emerging North-American outbreak in 2014. J Clin Virol 2015; 71:1-9. [PMID: 26364237 DOI: 10.1016/j.jcv.2015.07.296] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 07/13/2015] [Accepted: 07/16/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND In August and September 2014, unexpected clusters of enterovirus-D68 (EV-D68) infections associated with severe respiratory disease emerged from North-America. In September, the European Centre for Disease Prevention and Control (ECDC) asked European countries to strengthen respiratory sample screening for enterovirus detection and typing in cases with severe respiratory presentations. OBJECTIVES To provide a detailed picture of EV-D68 epidemiology in Europe by conducting a retrospective and prospective laboratory analysis of clinical specimens. STUDY DESIGN An initiative supported by the European Society for Clinical Virology (ESCV) and ECDC was launched to screen for EV-D68 in respiratory specimens between July 1st and December 1st 2014 in Europe and to sequence the VP1 region of detected viruses for phylogenetic analytic purposes. RESULTS Forty-two institutes, representing 51 laboratories from 17 European countries, analyzed 17,248 specimens yielding 389 EV-D68 positive samples (2.26%) in 14 countries. The proportion of positive samples ranged between 0 and 25% per country. These infections resulted primarily in mild respiratory disease, mainly detected in young children presenting with wheezing and in immuno-compromised adults. The viruses detected in Europe are genetically very similar to those of the North-American epidemic and the majority (83%) could be assigned to clade B. Except for 3 acute flaccid paralysis (AFP) cases, one death and limited ICU admissions, no severe cases were reported. CONCLUSIONS The European study showed that EV-D68 circulated in Europe during summer and fall of 2014 with a moderate disease burden and different pathogenic profile compared to the North-American epidemic.
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Affiliation(s)
- Randy Poelman
- The University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, Division of Clinical Virology, Groningen, The Netherlands.
| | - Isabelle Schuffenecker
- National Enterovirus Reference Centre, Laboratoire de Virologie, Centre de Biologie Est des Hospices Civils de Lyon, Bron, France
| | - Coretta Van Leer-Buter
- The University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, Division of Clinical Virology, Groningen, The Netherlands
| | - Laurence Josset
- National Enterovirus Reference Centre, Laboratoire de Virologie, Centre de Biologie Est des Hospices Civils de Lyon, Bron, France; Virpath Lab, EA4610, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon1, Université de Lyon, Lyon, France
| | - Hubert G M Niesters
- The University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, Division of Clinical Virology, Groningen, The Netherlands
| | - Bruno Lina
- National Enterovirus Reference Centre, Laboratoire de Virologie, Centre de Biologie Est des Hospices Civils de Lyon, Bron, France; Virpath Lab, EA4610, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon1, Université de Lyon, Lyon, France
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In Vitro Efficacy of Antiviral Compounds against Enterovirus D68. Antimicrob Agents Chemother 2015; 59:7779-81. [PMID: 26149998 DOI: 10.1128/aac.00766-15] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 07/03/2015] [Indexed: 02/07/2023] Open
Abstract
In 2014, the United States experienced a large outbreak of severe respiratory illness associated with enterovirus D68 (EV-D68). We used a homogeneous, cell-based assay to assess the antiviral activity of compounds developed for EV/rhinovirus infection or other indications. Three of 15 compounds were highly active against all four strains tested (the prototype and three 2014 strains), with 50% effective concentrations of 0.0012 to 0.027 μM. Additional studies are needed to assess their in vivo efficacy against EV-D68.
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Levy A, Roberts J, Lang J, Tempone S, Kesson A, Dofai A, Daley AJ, Thorley B, Speers DJ. Enterovirus D68 disease and molecular epidemiology in Australia. J Clin Virol 2015. [PMID: 26209392 DOI: 10.1016/j.jcv.2015.06.079] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Enterovirus D68 (EV-D68) has received considerable recent attention as a cause of widespread respiratory illness. Neurological syndromes such as acute flaccid paralysis following EV-D68 infection have also been reported in a small number of cases. OBJECTIVES To summarize the clinical and epidemiological characteristics of laboratory confirmed EV-D68 cases in Australia. STUDY DESIGN We combined EV-D68 data acquired through laboratory surveillance in Western Australia with cases from national enterovirus surveillance and regional acute flaccid paralysis (AFP) surveillance. Clinical data was obtained for EV-D68 cases and capsid protein sequences were used for phylogenetic analysis. RESULTS Sporadic cases of EV-D68 were recorded in Australia since 2008, with peaks in activity during 2011 and 2013. EV-D68 was primarily associated with respiratory disease, but was also detected in cerebrospinal fluid of one patient and faeces of two patients presenting with AFP. CONCLUSIONS EV-D68 has been circulating in Western Australia and is likely to have also been present in the wider region for a number of years, causing primarily respiratory disease. Detection of EV-D68 in cerebrospinal fluid of one patient and in faeces of two AFP cases reinforces the association between EV-D68 and neurological disease.
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Affiliation(s)
- Avram Levy
- PathWest Laboratory Medicine WA, Perth, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
| | - Jason Roberts
- National Enterovirus Reference Laboratory, VIDRL, Doherty Institute, Melbourne, Australia; School of Applied Sciences, RMIT University, Melbourne, Australia
| | - Jurissa Lang
- PathWest Laboratory Medicine WA, Perth, Australia
| | - Simone Tempone
- PathWest Laboratory Medicine WA, Perth, Australia; Current affiliate: Communicable Disease Control Directorate, Health Department of Western Australia, Perth, Australia
| | - Alison Kesson
- Department of Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child health and the Marie Bashir Institute for Emerging Infectious Diseases and Biosecurity, Sydney Medical School, Sydney, Australia
| | - Alfred Dofai
- National Referral Hospital, Honiara, Solomon Islands
| | - Andrew J Daley
- The Royal Children's Hospital, Melbourne, Australia; The University of Melbourne, Department of Paediatrics, Melbourne, Australia
| | - Bruce Thorley
- National Enterovirus Reference Laboratory, VIDRL, Doherty Institute, Melbourne, Australia; School of Applied Sciences, RMIT University, Melbourne, Australia
| | - David J Speers
- PathWest Laboratory Medicine WA, Perth, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia
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Enterovirus D68. A Focused Review and Clinical Highlights from the 2014 U.S. Outbreak. Ann Am Thorac Soc 2015; 12:775-81. [DOI: 10.1513/annalsats.201412-592fr] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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McAllister SC, Schleiss MR, Arbefeville S, Steiner ME, Hanson RS, Pollock C, Ferrieri P. Epidemic 2014 enterovirus D68 cross-reacts with human rhinovirus on a respiratory molecular diagnostic platform. PLoS One 2015; 10:e0118529. [PMID: 25799541 PMCID: PMC4370466 DOI: 10.1371/journal.pone.0118529] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 01/20/2015] [Indexed: 11/30/2022] Open
Abstract
Enterovirus D68 (EV-D68) is an emerging virus known to cause sporadic disease and occasional epidemics of severe lower respiratory tract infection. However, the true prevalence of infection with EV-D68 is unknown, due in part to the lack of a rapid and specific nucleic acid amplification test as well as the infrequency with which respiratory samples are analyzed by enterovirus surveillance programs. During the 2014 EV-D68 epidemic in the United States, we noted an increased frequency of “low-positive” results for human rhinovirus (HRV) detected in respiratory tract samples using the GenMark Diagnostics eSensor respiratory viral panel, a multiplex PCR assay able to detect 14 known respiratory viruses but not enteroviruses. We simultaneously noted markedly increased admissions to our Pediatric Intensive Care Unit for severe lower respiratory tract infections in patients both with and without a history of reactive airway disease. Accordingly, we hypothesized that these “low-positive” RVP results were due to EV-D68 rather than rhinovirus infection. Sequencing of the picornavirus 5’ untranslated region (5’-UTR) of 49 samples positive for HRV by the GenMark RVP revealed that 33 (67.3%) were in fact EV-D68. Notably, the mean intensity of the HRV RVP result was significantly lower in the sequence-identified EV-D68 samples (20.3 nA) compared to HRV (129.7 nA). Using a cut-off of 40 nA for the differentiation of EV-D68 from HRV resulted in 94% sensitivity and 88% specificity. The robust diagnostic characteristics of our data suggest that the cross-reactivity of EV-D68 and HRV on the GenMark Diagnostics eSensor RVP platform may be an important factor to consider in making accurate molecular diagnosis of EV-D68 at institutions utilizing this system or other molecular respiratory platforms that may also cross-react.
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Affiliation(s)
- Shane C. McAllister
- Division of Pediatric Infectious Diseases and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Infectious Disease and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- * E-mail:
| | - Mark R. Schleiss
- Division of Pediatric Infectious Diseases and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Infectious Disease and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Sophie Arbefeville
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Marie E. Steiner
- Division of Pediatric Hematology and Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Division of Pediatric Critical Care, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Ryan S. Hanson
- Division of Pediatric Infectious Diseases and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Infectious Disease and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Catherine Pollock
- Division of Pediatric Infectious Diseases and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Infectious Disease and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Patricia Ferrieri
- Division of Pediatric Infectious Diseases and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
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