Enterovirus D68: A clinically important respiratory enterovirus

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ABSTRACTSeasonal peaks of viral respiratory illnesses are common during late summer and early fall and have often been attributed to human rhinovirus. In the fall of 2014, the number of children hospitalized with severe lower respiratory symptoms and asthma suddenly increased, and the children tested positive by sequencing for enterovirus D68 (EV-D68). As the outbreak unfolded, a possible association was also observed between EV-D68 infection, polio-like acute flaccid paralysis, and cranial neuropathy in children.


  • EV-D68 is a respiratory virus that has genetic and biologic features that blur the distinction between the rhinoviruses and enteroviruses.
  • Recognition of EV-D68 as an important cause of viral lower respiratory tract illness in children underscores the role of specific strain typing in advancing our understanding of the epidemiology of respiratory virus infections.
  • Given the inability of commonly used clinical tests for rhinovirus to distinguish EV-D68 in the absence of strain-specific sequence data, caution needs to be used in attributing severe or acute lower respiratory illness to rhinovirus and in interpreting epidemiologic associations between asthma and rhinovirus.
  • Emerging data suggest that, in addition to its important role in pediatric respiratory illness, EV-D68 may cause systemic disease, especially acute neurologic disease.



In the fall of 2014, the United States experienced an outbreak of severe respiratory illness due to a virus of emerging importance, enterovirus D68 (EV-D68). Here, we review the features of this virus and related viruses, the clinical syndromes this virus causes, the epidemiology of the recent outbreak, and its diagnosis and treatment.


Originally identified in 1962 from the throat swab of a child with pneumonia, human EV-D68 has unique genetic and clinical features that blur the typical division between human enteroviruses and rhinoviruses.1–4 Enteroviruses and rhinoviruses are closely related species within the Picornaviridae family that are now classified together within the genus Enterovirus.5 Picornaviruses are small, nonenveloped, positive-stranded RNA viruses of medical significance.

Poliovirus: The first enterovirus discovered

The first human enterovirus to be discovered was poliovirus.6 Although sporadic cases of “infantile paralysis” occurred before the late 19th century, epidemic poliomyelitis abruptly appeared in Europe and the United States beginning around 1880. Before the introduction in 1955 of the inactivated poliovirus vaccine and then the oral poliovirus vaccine, polio was one of the most feared illnesses in the developed world. Outbreaks occurred primarily in cities during summer months. At its peak, epidemic polio killed or paralyzed more than half a million people a year.

One hypothesis to explain the sudden emergence of epidemic polio is that improved personal hygiene and public sanitation delayed the age at which children acquired this enteric infection.7 Infections acquired after infancy occurred in the absence of maternal antibodies that may have protected against the virus’s propensity to invade the nervous system.

Nonpolio human enteroviruses

In the decades since poliovirus was discovered, more than 100 nonpolio human enteroviruses have been recognized.8 This group includes the coxsackieviruses, echoviruses, and the newer numbered nonpolio human enteroviruses classified into four species, designated Human enterovirus A, B, C, and D. The last of these, Human enterovirus D, includes three serotypes known to cause disease in humans: EV-D68, EV-D70, and EV-D94.9

The genus Enterovirus includes the polioviruses; nonpolio enteroviruses A, B, C, and D; and rhinoviruses

As with poliovirus infection, most people infected with a nonpolio human enterovirus have a mild illness without distinctive features.5 In temperate climates, enteroviral infections are most common during the summer and fall and are an important cause of the “summer cold.” In tropical climates, the seasonal pattern is absent, and infections may occur throughout the year.

The clinical syndromes associated with a nonpolio human enterovirus can include nonspecific febrile illness; upper respiratory tract infection; pharyngitis; herpangina; hand, foot, and mouth syndrome; various skin exanthems; bronchiolitis; asthma exacerbation; gastrointestinal manifestations such as diarrhea and vomiting (which are especially common); more serious clinical syndromes such as hepatitis, pancreatitis, and cardiomyopathy; and neurologic illness, including aseptic meningitis, encephalitis, and polio-like paralytic disease.

Outbreaks caused by nonpolio human enteroviruses occur on a regular basis, may vary by strain from year to year, and often occur within a geographic region; multiple strains may circulate simultaneously. Occasionally, as with EV-D68 in August 2014 in the United States, epidemics can emerge suddenly and spread rapidly across the world, causing disease in hundreds or thousands of people, demonstrating the breadth of illness associated with particular strains.10


EV-D68 was first isolated in the United States from four children in Berkeley, California, who had lower respiratory tract symptoms (bronchiolitis and pneumonia) in 1962. The finding was published in the medical literature in 1967.1 Since its initial identification, EV-D68 was infrequently reported as a cause of human disease, with the US Centers for Disease Control and Prevention (CDC) listing only 26 cases in the 36 years from 1970 through 2005.11

However, the past decade has seen EV-D68 emerge as a significant respiratory pathogen, with more reports of acute respiratory illness associated with it in North America, Europe, and Asia, especially in children.12–17 A seasonal pattern may exist; a longitudinal survey of samples collected from New York City detected a focal outbreak in the fall of 2009.18

The observation that recent EV-D68 outbreaks have primarily been in children suggests that most adults have immunity to it. In this regard, seroepidemiologic studies from Finland demonstrated that most adults have neutralizing antibodies from previous infection.9

The blurred line between enteroviruses and rhinoviruses

Enteroviruses and rhinoviruses are typically distinguished on the basis of the temperature at which they grow best (rhinoviruses grow better at lower temperatures, allowing them to replicate in the nose) and their sensitivity to acidity (enteroviruses are more resistant, enabling them to survive in the stomach).

The original (“Fermon”) strain of EV-D68 isolated in 1962 was first classified as an enterovirus because it was resistant to low pH.1 However, when molecular sequencing became available, EV-D68 was found to be identical to human rhinovirus 87 (HRV87), a phylogenetic outlier among the rhinoviruses that binds to cells at a receptor site distinct from that of other human rhinoviruses.19

Thereafter, further testing showed that both EV-D68 and HRV87 isolates were sensitive to acid treatment by two different methods.4 Moreover, unlike most enteroviruses, EV-D68 behaves like a rhinovirus and grows preferentially at 33°C, the temperature of the nose.2

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