Review
Global emergence of enterovirus D68: a systematic review

https://doi.org/10.1016/S1473-3099(15)00543-5Get rights and content

Summary

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.

Introduction

Enterovirus D68 was first isolated in 1962 in Berkeley, CA, USA, from four children with severe respiratory tract infection and pneumonia.1 Since its initial identification, the virus has only been associated with sporadic cases of respiratory disease; only 26 cases were confirmed in the USA between 1970 and 2005.2 Minor outbreaks of enterovirus D68 were also described, with 699 cases confirmed in Europe, Africa, and southeast Asia between 1970 to 2013.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 In late summer of 2014 a large-scale outbreak of enterovirus D68 causing severe respiratory infection mainly in children was noted in the USA and Canada, with subsequent reports from other countries. So far, 2287 cases of enterovirus D68 infection in 2014 have been published.7, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51

Enteroviruses are small single-stranded RNA viruses in the Picornaviridae family that share similar morphology, structure, molecular properties, and replication strategies.52, 53 All viruses in the Picornaviridae family are small (18–30 nm), non-enveloped, and single-stranded positive-sense RNA viruses.54 Enteroviruses cause more than 10 million infections and several thousand hospital admissions every year in the USA alone and, together with human rhinoviruses, are among the most common pathogens associated with human disease.34, 52, 55 Enteroviruses are major contributors to disease worldwide, with a wide range of clinical features ranging from very mild to fatal infections.52 Enteroviruses are commonly involved in both acute and chronic cardiac disease; hand, foot, and mouth disease; respiratory infections; herpangina; myositis; pleurodynia; eye infections including acute haemorrhagic conjunctivitis; encephalitis; aseptic meningitis; and acute flaccid paralysis. Recently investigators have suggested that enterovirus infection combined with specific genetic host factors can trigger insulin-dependent diabetes in susceptible individuals.54 The most well known enterovirus is poliovirus, the cause of poliomyelitis. Despite the eradication of poliovirus in most parts of the world, the disease remains of great concern because of its potential to spread and cause large outbreaks with high mortality and disability. In 2015, reported cases of wild poliovirus have been low with only 102 cases reported worldwide, 77 in endemic countries (Afghanistan and Pakistan) and 25 in non-endemic countries (Guinea, Laos, Madagascar, Myanmar, Nigeria, and Ukraine).56

Enterovirus D68 belongs to the species enterovirus D, which consists of four human genotypes: enterovirus D68, enterovirus D70, enterovirus D94, and enterovirus D111, as well as the genotype enterovirus D120 recently identified in the stool of apes.54, 57, 58 Human rhinovirus 87 was reclassified as a strain of enterovirus D68 in 2002, and is therefore of great importance when studying its historic emergence. Enterovirus D68 is a unique genotype that differs somewhat from most enteroviruses, sharing more physiochemical properties with human rhinoviruses.23, 59, 60 Furthermore, enterovirus D68 differs from other enteroviruses in temperature sensitivity, growing in cell culture at 33°C, which is the temperature of the nose, rather than at 37·0°C.59, 61 Enterovirus D68 has mainly been isolated from respiratory samples, and has very rarely been reported in stools.3, 7, 37 Additionally, enterovirus D68 has a short C-terminal α helix in the VP3 protein not present in other enteroviruses.62 Three primary clades (A, B, and C) have been identified by Bayesian phylogenetic analysis of the VP1 region. Although all three clades are distributed globally, most of the observed diversity within enterovirus D68 has been reported from the USA.26 However, the enterovirus D68 phylogeny is characterised by the frequent presence of long branches throughout the tree, indicative of a general absence of global surveillance and detection of enterovirus D68, as well as the presence of in-situ evolution in individual locations. Retrospective or broader sampling could reveal additional (and deeper) diversity.26

The unprecedented outbreak of enterovirus D68 in the autumn of 2014, which resulted in an upsurge of hospitalisations and admissions to intensive-care units, has prompted concern about a potential uncontrollable epidemic of severe lower respiratory diseases and neurological complications, including muscle weakness, polio-like acute flaccid paralysis, and cranial neuropathy.38, 39, 49, 51, 63, 64, 65, 66, 67 The 2014 outbreak was extensive; 1153 identified cases of severe respiratory disease and 107 cases of acute flaccid myelitis were reported in September to December, 2014, in the USA alone.7, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 68 Furthermore, nearly 700 cases were confirmed in Canada, including eight cases of acute flaccid paralysis and other neurological diseases, two cases in Chile, and 408 cases in Europe, including three children with complications of acute flaccid paralysis in France and Norway.32, 35, 36, 37, 38, 40, 41, 43, 44, 45, 46, 47, 48, 49, 51, 67, 69 25 cases have been reported in China, Taiwan, and Thailand.7, 30, 31, 47 These cases have subsequently all been attributed to enterovirus D68 infection.7, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 Due to the testing practices of enteroviruses in respiratory material, which we detail in this Review, the cases presented are most probably a small proportion of actual cases that have occurred. In this systematic review we aimed to use the published work to investigate the potential of enterovirus D68 to cause severe respiratory infection and neurological symptoms in children.

Section snippets

Search strategy and selection criteria

We used the 2009 PRISMA guidelines to systematically review the literature for enterovirus D68. We searched PubMed for reports published from 1962 to Aug 18, 2015, with the terms “enterovirus 68”, “enterovirus D68”, and “EV D68”, without MeSH terms. We reviewed all available published work. All studies were published in peer-reviewed journals, apart from data from the Canadian health authorities. We used no language restrictions, and data from abstracts from Spanish and Chinese studies were

Historical outbreaks from 1962 to January, 2014

Before 2014 enterovirus D68 was one of the rarest identified enteroviruses.26 After its first identification in 1962 cluster outbreaks of respiratory disease caused by enterovirus D68 were reported in the USA, Europe, southeast Asia, and Africa. 699 cases of enterovirus D68 were reported up to the beginning of 2014 (table 1).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 Most of these cases have been identified

The major enterovirus D68 outbreak in 2014

In the autumn of 2014 (between August and December; table 2), an unprecedented high number of people (almost all children) were admitted to hospitals across the USA, Canada, and Europe with severe lower respiratory disease. This outbreak was the largest since the identification of enterovirus D68, with 2287 cases confirmed worldwide in 2014.3, 7, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 From the USA alone, 1153 cases were reported in 49 states from

Clinical presentation

Enterovirus D68 can cause a wide range of respiratory disorders in children, from pharyngitis and bronchitis to the more severe pneumonia and respiratory failure (figure 2).1, 13, 59, 62 Healthy adults can become infected with enterovirus D68 too, although they usually present with a milder range of respiratory symptoms. However, severe disease has been reported in adults including severe acute respiratory distress syndrome in an otherwise healthy woman aged 25 years in whom mechanical

Hospitalisations and deaths

Patients who were severely affected by enterovirus D68 infection can need admission to hospital and further treatment in an intensive-care unit, including mechanical ventilation support.5, 15, 23, 24, 35, 36, 38, 40, 41, 43, 46, 48, 49, 61, 72 In 2014, 14 deaths in the USA were associated with enterovirus D68 infection, 1% of cases reported (table 2).34, 41 The Cleveland Clinic reports that more than 45% of children identified with a respiratory enterovirus needed treatment and observation in

Underlying disease

Underlying disease is a risk factor for severe respiratory disease for both children and adults. Patients immunocompromised due to transplants, patients with chronic obstructive pulmonary disease, and underlying asthma are at increased risk.43 Of 195 children for whom specific data are available (figure 2), at least 60 (31%) had underlying disorders, but not all studies provided information on these diseases.1, 6, 8, 9, 11, 15, 20, 21, 22, 24, 25, 35, 36, 40, 43, 45, 47, 50

Asthma was the most

Acute flaccid paralysis

Acute flaccid paralysis is a complex clinical syndrome with sudden onset of limb weakness in one or more limbs or the respiratory and bulbar muscles as a result of damage of the lower motor neurons.63, 66 Acute flaccid paralysis is one of the most devastating and disabling complications of poliovirus and other non-polio enteroviruses, and surveillance for acute flaccid paralysis is the gold standard for monitoring of polio.75 Monitoring includes finding and reporting children with acute flaccid

Treatment

No treatment is available for acute flaccid paralysis related to enterovirus D68. Three antiviral drugs—pleconaril (NCT00031512 and NCT00394914), pocapavir, and vapendavir (NCT02367313 and EUCTR2014-001785-95-CZ)—are being clinically tested for enteroviral infections. Pleconaril inhibits enterovirus D68 by stabilising the capsid and preventing uncoating of the viral particle during cell entry.62 Other novel studies show that fluoxetine also might inhibit the replication of enterovirus D68.62, 68

Discussion

Enterovirus 68 was first identified in 1962 and up to 2014 few cases were reported. In the autumn of 2014 a large outbreak in the USA and Canada was reported, which led to an increased awareness and scaling up of surveillance in other parts of the world. At the time of publication, 2287 cases of enterovirus D68 have been reported to have occurred in 2014.7, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49

The 2014 enterovirus D68 outbreak has led to an increased

Conclusions and future actions

Enterovirus D68 differs from other enteroviruses virologically, including physical and chemical properties, and epidemiologically.22, 51, 59, 60 It is uncertain whether the increased incidence of enterovirus D68 in the autumn of 2014 was a one-time epidemic or whether the increased incidence in the past 10 years suggests that enterovirus D68 is establishing itself as an emerging pathogen. Either way, the recent epidemic and the potential for endemic transmission indicates the need for better

References (82)

  • AL Greninger et al.

    A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012–14): a retrospective cohort study

    Lancet Infect Dis

    (2015)
  • K Messacar et al.

    A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA

    Lancet

    (2015)
  • A Mirand et al.

    Acute flaccid myelitis and enteroviruses: an ongoing story

    Lancet

    (2015)
  • JE Schuster et al.

    Severe enterovirus 68 respiratory illness in children requiring intensive care management

    J Clin Virol

    (2015)
  • A Waghmare et al.

    Clinical disease due to enterovirus D68 in adult hematologic malignancy patients and hematopoietic cell transplant recipients

    Blood

    (2015)
  • JH Schieble et al.

    A probable new human picornavirus associated with respiratory diseases

    Am J Epidemiol

    (1967)
  • N Khetsuriani et al.

    Enterovirus surveillance—United States, 1970-2005

    MMWR Surveill Summ

    (2006)
  • S Carney et al.

    Enterovirus D68 detected in children with severe acute respiratory illness in Brazil

    Emerg Microbes Infect

    (2015)
  • Clusters of acute respiratory illness associated with human enterovirus 68–Asia, Europe, and United States, 2008–2010

    MMWR Morb Mortal Wkly Rep

    (2011)
  • S Hasegawa et al.

    Enterovirus 68 infection in children with asthma attacks: virus-induced asthma in Japanese children

    Allergy

    (2011)
  • YP Huang et al.

    Molecular and epidemiological study of enterovirus D68 in Taiwan

    J Microbiol Immunol Infect

    (2015)
  • T Ikeda et al.

    Acute respiratory infections due to enterovirus 68 in Yamagata, Japan between 2005 and 2010

    Microbiol Immunol

    (2012)
  • T Imamura et al.

    Enterovirus 68 among children with severe acute respiratory infection, the Philippines

    Emerg Infect Dis

    (2011)
  • LM Jacobson et al.

    Outbreak of lower respiratory tract illness associated with human enterovirus 68 among American Indian children

    Pediatr Infect Dis J

    (2012)
  • A Kaida et al.

    Enterovirus 68 in children with acute respiratory tract infections, Osaka, Japan

    Emerg Infect Dis

    (2011)
  • JD Kreuter et al.

    A fatal central nervous system enterovirus 68 infection

    Arch Pathol Lab Med

    (2011)
  • IL Lauinger et al.

    Lineages, sub-lineages and variants of enterovirus 68 in recent outbreaks

    PLoS One

    (2012)
  • C Launes et al.

    Molecular epidemiology of severe respiratory disease by human rhinoviruses and enteroviruses at a tertiary paediatric hospital in Barcelona, Spain

    Clin Microbiol Infect

    (2015)
  • P Linsuwanon et al.

    Molecular epidemiology and evolution of human enterovirus serotype 68 in Thailand, 2006–2011

    PLoS One

    (2012)
  • N Ly et al.

    Multiplex PCR analysis of clusters of unexplained viral respiratory tract infection in Cambodia

    Virol J

    (2014)
  • A Meijer et al.

    Continued seasonal circulation of enterovirus D68 in the Netherlands, 2011–2014

    Euro Surveill

    (2014)
  • KT Ng et al.

    Outbreaks of enterovirus D68 in Malaysia: genetic relatedness to the recent US outbreak strains

    Emerg Microbes Infect

    (2015)
  • SM Opanda et al.

    Genetic diversity of human enterovirus 68 strains isolated in Kenya using the hypervariable 3′-end of VP1 gene

    PLoS One

    (2014)
  • A Piralla et al.

    Phylogenetic characterization of enterovirus 68 strains in patients with respiratory syndromes in Italy

    J Med Virol

    (2014)
  • QB Lu et al.

    Detection of enterovirus 68 as one of the commonest types of enterovirus found in patients with acute respiratory tract infection in China

    J Med Microbiol

    (2014)
  • J Rahamat-Langendoen et al.

    Upsurge of human enterovirus 68 infections in patients with severe respiratory tract infections

    J Clin Virol

    (2011)
  • F Renois et al.

    Enterovirus 68 in pediatric patients hospitalized for acute airway diseases

    J Clin Microbiol

    (2013)
  • AK Todd et al.

    Detection and whole genome sequence analysis of an enterovirus 68 cluster

    Virol J

    (2013)
  • R Tokarz et al.

    Worldwide emergence of multiple clades of enterovirus 68

    J Gen Virol

    (2012)
  • R Tokarz et al.

    Longitudinal molecular microbial analysis of influenza-like illness in New York City, May 2009 through May 2010

    Virol J

    (2011)
  • Z Wang et al.

    Broad spectrum respiratory pathogen analysis of throat swabs from military recruits reveals interference between rhinoviruses and adenoviruses

    Microb Ecol

    (2010)
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