Enterovirus D68: A clinically important respiratory enterovirus
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.
KEY POINTS
- 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.
How enterovirus D68 enters cells
Viral surface proteins, including hemagglutinin, from certain respiratory viruses have the ability to bind sugars on cells in the nose and lungs, which facilitates viral entry and replication. EV-D68 binds specifically to alpha 2-6 sialic acid, the predominant sialic acid found in the human upper respiratory tract.19,20 The absence of EV-D68 binding affinity for alpha 2-3 sialic acid, present in ciliated epithelial cells of the lower tract, suggests that alternative mechanisms may be responsible for the severe lower respiratory disease associated with this virus.
Entry of EV-D68 into cells requires additional mediators. EV-D70 belongs to the same genetic cluster as EV-D68 and enters HeLa cells using decay-accelerating factor (DAF).21 Evidence that EV-D68 also uses DAF for cell entry comes from experiments showing that monoclonal antibodies against DAF inhibit the cytopathic effects of this virus.4 Virus-receptor interactions have been more thoroughly characterized for other enteroviruses.22 In this regard, coxsackieviruses of group B use DAF as a coreceptor. Since DAF is expressed at high levels in both epithelial and endothelial cells, it may play an important role in the induction of the viremia that precedes the infection of specific tissues such as the heart or pancreas.
Different strains exist
EV-D68 strains can be divided into three genetic groups based on the sequence of the capsid-coding VP1 region, the most variable genome region of enteroviruses.23
Investigators have explored whether emergent EV-D68 strains differ in their anti-
genicity and receptor-binding properties in comparison to the Fermon strain isolated in 1962.20 Using antisera generated from various strains of EV-D68, significant differences were observed in terms of hemagglutination inhibition and neutralization titers both between emergent strains and the original Fermon strain and among the emergent strains.
Viremia in systemic disease
Like other enteroviruses, EV-D68 has the ability to infect lymphocytes.9 This may provide a mechanism by which the virus is transported during the viremic phase to secondary target organs. Indeed, EV-D68 was detected in the serum of 12 (43%) of 28 pediatric patients with pneumonia and positive nasopharyngeal swabs.24
Interestingly, whether EV-D68 was detected in the serum varied with age. Viremia was not detected in the serum of children younger than 1 year, an observation suggesting that maternal antibodies protect against viremia.
The role of viremia in systemic disease associated with EV-D68 is intriguing, especially since delayed acquisition of polio infection beyond infancy is hypothesized to have contributed to disease severity.7
ENTEROVIRUS D68 CAUSES SEVERE LOWER RESPIRATORY DISEASE
While identification of large numbers of patients with respiratory illnesses due to EV-D68 in a single season is unique to 2014, clusters of EV-D68-related respiratory illnesses have previously been recognized.25,26
As with EV-D68 outbreaks in other parts of the world, the outbreak in the US Midwest in August 2014 primarily involved children, many of whom needed to be admitted to the hospital because of severe lower respiratory symptoms.10 In the 30 children admitted to two children’s hospitals described in the initial report, difficulty breathing, hypoxemia, and wheezing were common. A minority of patients (23%) presented with fever. Of hospitalized children, 67% required admission to the intensive care unit. Two patients required intubation, including one who required extracorporeal membrane oxygenation. Six required bilevel positive airway pressure therapy.
Cleveland Clinic experience
At Cleveland Clinic during the same time, nearly 45% of patients identified with a respiratory enterovirus infection required intensive care.
For patients previously diagnosed with asthma, chronic lung disease, or wheezing, essential supportive care measures included continuing the inhaled steroids the patients were already taking, early use of short-acting beta agonists, and, in those with previously diagnosed asthma, consideration of a systemic steroid. Many of our patients with previously diagnosed asthma had an unusually long prodrome of an increase in mild symptoms, followed by a rapid and severe decline in respiratory status.
At the later phase, supportive care measures that were needed included maintenance of hydration and monitoring of oxyhemoglobin saturation with use of supplemental oxygen as necessary, as well as close observation of clinical indicators of respiratory distress, such as development of crackles, asymmetric air exchange, and progression in wheezing or in use of accessory muscles. In an attempt to avoid invasive ventilatory support in patients with asthma or other comorbid conditions, some patients were treated with aerosolized epinephrine, ipratropium, heliox, and noninvasive positive pressure ventilatory support.
