ReviewGlobal emergence of enterovirus D68: a systematic review
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
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