That other EVD: Enterovirus-D68 – what’s it all about?

Until recently, we suspect that very few of those reading the present article were familiar with the D68 serotype of enterovirus. However, starting in August 2014, reports arose of severe respiratory disease in children with enterovirus D68 (EV-D68) in both Chicago, Illinois, and Kansas City, Kansas (USA) (Table 1) (1), right in the midst of concerns worldwide about a more virulent pathogen that is also abbreviated as EVD – Ebola virus disease. In 2012, the taxonomy for the genus Enterovirus, belonging to the family Picornaviridae, was revised to include 12 species: enterovirus A though J (with no letter ‘I’ because it could be confused with the number one) and rhinovirus A, B and C (2). Each of the 12 species is subdivided into serotypes that are named using an abbreviation of the appropriate common virus name (with the human ones being enterovirus [EV], coxsackievirus [CV], echovirus [E], poliovirus [PV] and rhinovirus [RV]) and a number (3). Most of the human pathogens belong to E enterovirus A through D. To make the nomenclature even more confusing, most commercial laboratory respiratory virus testing methods use multiplex polymerase chain reaction (PCR) assays that do not distinguish between enterovirus and rhinovirus, often resulting in the grouping of these viruses in laboratory reports. EV-D68, belonging to E enterovirus D, was first detected in 1962 in four children in California (USA)with respiratory disease (4). Since then, clusters of cases of respiratory disease linked to EV-D68 have been described worldwide (Table 1). EV-D68 was initially named human rhinovirus 87 because it has the acid liability typical of rhinovirus (5), until genetic and antigenic analysis led to it being reclassified as an enterovirus (6). Voluntary and passive enterovirus surveillance in the United States (US) from 1970 through 2005 identified EV-D68 as a rare serotype (ranked 47th of 58 serotypes identified), with one unusual feature being that only one-half of the 26 cases occurred during the typical US enteroviral season (June through October). The percentage of cases occuring among individuals ≥20 years of age (23.5%) was higher than for most enteroviral serotypes (7). Despite the fact that apparent outbreaks with severe clinical manifestations have occurred on different continents for >50 years, the epidemiology of EV-D68 is far from fully elucidated. Most clinicians only obtained access to routine diagnostics for enterovirus when molecular detection methods became widely available in the past decade. As previously mentioned, laboratories commonly do not distinguish between enterovirus and rhinovirus. Even when these viruses are differentiated, enterovirus serotyping is typically only available as part of an outbreak investigation. Therefore, the incidence of EV-D68 infection, the spectrum of clinical manifestations, the ages of those with infection and disease, and both shortand long-term outcomes are unclear. Why was there so much more ‘fuss’ about the 2014 EV-D68 clusters of cases compared with previous outbreaks? It appears likely that this heightened level of concern occurred because, due to more rapid availability of strain typing, the virus linked to the US clusters was identified before the outbreak had passed. Furthermore, to have simultaneous outbreaks with multiple pediatric intensive care admissions in US cities that are 700 km apart was alarming, indicating that we could be on the verge of a widespread severe outbreak. In response to the reports of the two US outbreaks, the Provincial Laboratory for Public Health in Alberta retrospectively tested 230 nasopharyngeal specimens from children (<18 years of age) submitted from July 1, 2014 to September 10, 2014 from which enterovirus or rhinovirus had already been detected. None of the specimens from July yielded enterovirus. There were 83 enterovirus specimens from August and September, of which 49 (59%) proved to be D68. As of November 7, 2014, an additional 62 cases of EV-D68 in Alberta have been detected in children through prospective testing (8). In the US, almost all states (47 of 50) reported cases of EV-D68 as of November 12, 2014, with a total of 1116 cases detected. EV-D68 was clearly the predominant serotype because it was detected from approximately 40% of all specimens submitted to the US Centers for Disease Control and Prevention (CDC) (Georgia, USA) for enteroviral testing, with approximately 30% being positive for other enteroviruses or rhinovirus (9). Asthma appeared to be a risk factor for the detection of EV-D68 in Alberta and in the US (8,9). This link had not been described with previous outbreaks, possibly because they were dramatically smaller. Other than children in the two index outbreaks in Chicago and Kansas City (1), it appears that most children in whom EV-D68 was detected in 2014 experienced uneventful hospital admission with respiratory tract infections. One would assume that if EV-D68 is similar to all other enteroviruses, patients in whom EV-D68 is detected represent ‘the tip of the iceberg’, with many others not being tested because they did not require hospital admission, did not have testing performed or did not have symptoms that would prompt testing for respiratory viruses. Anecdotally, pediatric emergency physicians in Alberta described seeing more severe cases of asthma in August and September than expected for that time of year, but it is not possible to determine whether this was related to EV-D68. Twelve deaths had been reported in the US as of November 12, 2014 (9) but the clinical details and the role that EV-D68 played in these deaths is unclear. To further muddy the waters, on September 24, 2014, the CDC announced that nine children in Colorado (USA) had presented from August 8 to September 15, 2014 with acute flaccid paralysis (AFP), of whom four ultimately had EV-D68 detected from nasopharyngeal specimens (10). Features of these cases that were unusual for AFP included focal extremity involvement and magnetic resonance imaging changes in the anterior horn cells, specifically nonenhancing lesions on multiple levels of the spinal cord usually restricted to the gray matter (anterior myelitis). Of note, of 245 cases of AFP in California from 1992 to 1998, none had anterior myelitis documented on imaging (11). In response to the Colorado cases, the CDC began performing surveillance for cases of AFP with onset August 1, 2014 or later that had focal limb weakness and anterior myelitis on magnetic resonance imaging. As of November 12, 2014, 75 cases of AFP from 29 states had been reported through this surveillance program (12). In Canada, it became evident that most pediatric hospitals had also admitted a small number of similar AFP cases, including at least four cases in Calgary (Alberta) (13) and two in Edmonton (Alberta). As with the Colorado cases, many did not have EV-D68 detected. It is not pediatric infectious diseases notes