What has caused the recent emergence of enterovirus D68 and other pathogenic enteroviruses?

Project Overview

Seroprevalence of EV-D68 in different age groups before and after the outbreak of 2014-2016

Enteroviruses are extraordinarily prevalent and genetic diverse viruses that cause widespread often endemic infection in human populations worldwide. Disease manifestations and severities vary substantially ranging from unapparent infections to meningitis, endocarditis and poliomyelitis. Disease outcomes from EV infections vary over time, with several examples of recently emerged pathogenic viruses, such as EV-A71 in South and East Asia and more recently EV-D68. This is a widely prevalent picornavirus causing generally mild or non-symptomatic upper respiratory tract infections in humans. Recently, however, infections have been associated with outbreaks of much more severe respiratory disease, and in a number of cases, a temporary or permanent paralysis arising from viral invasion of the central and peripheral nervous system (1-4). This apparent change in pathogenicity and cellular tropism for cells in the CNS may be linked to the emergence of novel genetically distinct EV-D68 variants. Alternatively, the increased number of severe cases may reflect larger-scale changes in population immunity that have enabled outbreaks to occur in potentially vulnerable age groups. Recent modelling of seroprevalence data from a range of other enteroviruses has allowed these factors to be disentangled, and provide evidence for both changes in population immunity and changes in the biological properties of the viruses themselves underlying recent outbreaks of EV-associated disease (5).

The project to be undertaken for the DPhil will investigate underlying causes of enterovirus emergence through a combination of laboratory-based data generation on seroprevalence and virus phenotypic properties, the incorporation of surveillance data from the recently established European non-poliovirus network (ENPEN, Heli Harvala) and the application of modelling methods to make predictions on virus incidence and biological changes (Nick Grassly and colleagues, Imperial College).


1. Holm-Hansen CC, Midgley SE, Fischer TK. Global emergence of enterovirus D68: a systematic review. The Lancet Infectious diseases. 2016 May;16(5):e64-75.

2. Sejvar JJ, Lopez AS, Cortese MM, Leshem E, Pastula DM, Miller L, et al. Acute Flaccid Myelitis in the United States, August-December 2014: Results of Nationwide Surveillance. Clin Infect Dis. 2016 Sep 15;63(6):737-45.

3. Pfeiffer HC, Bragstad K, Skram MK, Dahl H, Knudsen PK, Chawla MS, et al. Two cases of acute severe flaccid myelitis associated with enterovirus D68 infection in children, Norway, autumn 2014. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2015 Mar 12;20(10):21062.

4. Kirolos A, Mark K, Shetty J, Chinchankar N, McDougall C, Eunson P, et al. Outcome of paediatric acute flaccid myelitis associated with enterovirus D68: a case series. Developmental medicine and child neurology. 2018 Nov 12.

5. Pons-Salort M, Grassly NC. Serotype-specific immunity explains the incidence of diseases caused by human enteroviruses. Science. 2018 Aug 24;361(6404):800-3.

Training Opportunities

The DPhil will provide experience and training in a wide range of laboratory virology methods, public health surveillance methods and data handling and modelling. These include:

The work is at the forefront of investigations of EV outbreaks of increasing public health importance. Underlying root causes for changes in EV disease patterns is high relevant to the justification and design of future immunisation and other prevention strategies.



Immunology & Infectious Disease and Genetics & Genomics


Project reference number: 1025

Funding and admissions information


Name Department Institution Country Email
Professor Peter Simmonds Experimental Medicine Division Oxford University, Peter Medawar Building GBR peter.simmonds@ndm.ox.ac.uk
Professor Peter Horby Tropical Medicine Oxford University, Old Road Campus Research Building GBR peter.horby@ndm.ox.ac.uk

Holm-Hansen CC, Midgley SE, Fischer TK. 2016. Global emergence of enterovirus D68: a systematic review. Lancet Infect Dis, 16 (5), pp. e64-e75. Read abstract | Read more

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. Hide abstract

Sejvar JJ, Lopez AS, Cortese MM, Leshem E, Pastula DM, Miller L, Glaser C, Kambhampati A, Shioda K, Aliabadi N, Fischer M, Gregoricus N, Lanciotti R, Nix WA, Sakthivel SK, Schmid DS, Seward JF, Tong S, Oberste MS, Pallansch M, Feikin D. 2016. Acute Flaccid Myelitis in the United States, August-December 2014: Results of Nationwide Surveillance. Clin. Infect. Dis., 63 (6), pp. 737-745. Read abstract | Read more

BACKGROUND: During late summer/fall 2014, pediatric cases of acute flaccid myelitis (AFM) occurred in the United States, coincident with a national outbreak of enterovirus D68 (EV-D68)-associated severe respiratory illness. METHODS: Clinicians and health departments reported standardized clinical, epidemiologic, and radiologic information on AFM cases to the Centers for Disease Control and Prevention (CDC), and submitted biological samples for testing. Cases were ≤21 years old, with acute onset of limb weakness 1 August-31 December 2014 and spinal magnetic resonance imaging (MRI) showing lesions predominantly restricted to gray matter. RESULTS: From August through December 2014, 120 AFM cases were reported from 34 states. Median age was 7.1 years (interquartile range, 4.8-12.1 years); 59% were male. Most experienced respiratory (81%) or febrile (64%) illness before limb weakness onset. MRI abnormalities were predominantly in the cervical spinal cord (103/118). All but 1 case was hospitalized; none died. Cerebrospinal fluid (CSF) pleocytosis (>5 white blood cells/µL) was common (81%). At CDC, 1 CSF specimen was positive for EV-D68 and Epstein-Barr virus by real-time polymerase chain reaction, although the specimen had >3000 red blood cells/µL. The most common virus detected in upper respiratory tract specimens was EV-D68 (from 20%, and 47% with specimen collected ≤7 days from respiratory illness/fever onset). Continued surveillance in 2015 identified 16 AFM cases reported from 13 states. CONCLUSIONS: Epidemiologic data suggest this AFM cluster was likely associated with the large outbreak of EV-D68-associated respiratory illness, although direct laboratory evidence linking AFM with EV-D68 remains inconclusive. Continued surveillance will help define the incidence, epidemiology, and etiology of AFM. Hide abstract

Pfeiffer HC, Bragstad K, Skram MK, Dahl H, Knudsen PK, Chawla MS, Holberg-Petersen M, Vainio K, Dudman SG, Kran AM, Rojahn AE. 2015. Two cases of acute severe flaccid myelitis associated with enterovirus D68 infection in children, Norway, autumn 2014. Euro Surveill., 20 (10), pp. 21062. Read abstract | Read more

Enterovirus D68 (EV-D68), phylogenetic clade B was identified in nasopharyngeal specimens of two cases of severe acute flaccid myelitis. The cases were six and five years-old and occurred in September and November 2014. EV-D68 is increasingly associated with acute flaccid myelitis in children, most cases being reported in the United States. Awareness of this possible neurological complication of enterovirus D68 infection is needed. Hide abstract

Kirolos A, Mark K, Shetty J, Chinchankar N, Mcdougall C, Eunson P, Stevenson J, Templeton K, NHS Lothian EV-D68 Associated AFM Study Group. 2019. Outcome of paediatric acute flaccid myelitis associated with enterovirus D68: a case series. Dev Med Child Neurol, 61 (3), pp. 376-380. Read abstract | Read more

Enterovirus D68 (EV-D68) is an emerging infection associated with acute flaccid myelitis (AFM). Cases of AFM associated with EV-D68 infection have increased in recent years and the evidence for a causal link is growing. However, our understanding of the epidemiology, clinical features, prognosis, and neurological sequelae of EV-D68 requires ongoing surveillance and investigation. We report five cases of AFM in previously typically developing children (2-6y) from South East Scotland during September and October 2016 after infection with EV-D68 (all detected in the nasopharyngeal aspirates). All cases presented with significant neurological symptoms, which were severe in two cases requiring intensive care support because of respiratory paralysis. At 18-month follow-up, two cases remain ventilator-dependent with other cases requiring ongoing community rehabilitation. These cases represent one of the largest reported paediatric cluster of AFM associated with EV-D68 in Europe. The epidemiology and clinical information add to the knowledge base and the 18-month outcome will help clinicians to counsel families. WHAT THIS PAPER ADDS: Nasopharyngeal aspirate is more sensitive for viral isolation and isolated in all cases. Clinical outcome at 18 months after enterovirus D68 with acute flaccid myelitis provides information on extent of recovery and level of disability. Hide abstract

Pons-Salort M, Grassly NC. 2018. Serotype-specific immunity explains the incidence of diseases caused by human enteroviruses. Science, 361 (6404), pp. 800-803. Read abstract | Read more

Human enteroviruses are a major cause of neurological and other diseases. More than 100 serotypes are known that exhibit unexplained complex patterns of incidence, from regular cycles to more irregular patterns, and new emergences. Using 15 years of surveillance data from Japan (2000-2014) and a stochastic transmission model with accurate demography, we show that acquired serotype-specific immunity can explain the diverse patterns of 18 of the 20 most common serotypes (including Coxsackieviruses, Echoviruses, and Enterovirus-A71). The remaining two serotypes required a change in viral characteristics, including an increase in pathogenicity for Coxsackievirus-A6, which is consistent with its recent global rise in incidence. On the basis of our findings, we are able to predict outbreaks 2 years ahead of time (2015-2016). These results have implications for the impact of vaccines under development. Hide abstract