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Enterovirus D68: A clinically important respiratory enterovirus

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NEUROLOGIC DISEASE: ACUTE FLACCID PARALYSIS

Although EV-D68 causes primarily respiratory illness, systemic disease occurs, especially neurologic involvement.

Before the recent outbreak of EV-D68, two cases of neurologic involvement from EV-D68 were reported. The first of these, mentioned in a 2006 enterovirus surveillance report issued by the CDC, was in a young adult with acute flaccid paralysis and EV-D68 isolated from the cerebral spinal fluid.11 In the second case, from 2010, a 5-year-old boy developed fatal meningomyeloencephalitis. The child had presented with pneumonia and acute flaccid paralysis. EV-D68 was identified in his cerebral spinal fluid by polymerase chain reaction (PCR), and histopathologic study of the meninges, cerebellum, midbrain, pons, medulla, and cervical cord demonstrated extensive T-cell lymphocytic meningomyelitis and encephalitis, characterized by prominent neuronophagia in motor nuclei.27

At the same time as the recent outbreak of EV-D68 respiratory disease, neurologists throughout the United States observed an increase in the number of children with polio-like acute flaccid paralysis. On September 26, 2014, the CDC issued an alert describing acute neurologic illness with focal limb weakness of unknown etiology in children, possibly associated with EV-D68.28 The report described nine cases of an acute neurologic illness in children ages 1 through 18 years (median age, 10) hospitalized in Colorado between August 9 and September 17, 2014. Common clinical features included acute focal limb weakness and paralysis and acute cranial nerve dysfunction, with no altered mental status or seizures. Pain before the onset of weakness was also identified as a common complaint.

Specific findings on magnetic resonance imaging of the spinal cord consisted of nonenhancing lesions largely restricted to the gray matter and in most cases spanning more than one level of the spinal cord. In patients with cranial nerve dysfunction, correlating nonenhancing brainstem lesions were observed.

Neurologists observed an increase in the number of children with polio-like acute flaccid paralysis

Most children experienced a febrile respiratory illness in the 2 weeks preceding the onset of neurologic symptoms. In most cases, cerebrospinal fluid analyses demonstrated mild or moderate pleocytosis consistent with an inflammatory or infectious process, with normal to mildly elevated protein and normal glucose levels. In six of the eight patients tested, nasopharyngeal specimens were positive for rhinovirus-enterovirus. Of the six positive specimens, at least four were typed as EV-D68.

The CDC also reported a second cluster of cases of acute flaccid paralysis with anterior myelitis on magnetic resonance imaging, in 23 children (mean age 10 years) in California from June 2012 to June 2014.29 No common cause was identified, although clinical and laboratory findings supported a viral etiology. Two patients tested positive for EV-D68 from upper respiratory tract specimens. Common features among the clinical presentations included an upper respiratory or gastrointestinal prodrome less than 10 days before the onset of the paralysis (83%), cerebrospinal fluid pleocytosis (83%), and absence of sensory deficits (78%). Ten patients (43%) also had concomitant mental status changes, and eight (34%) had cranial nerve abnormalities.

Details regarding outcomes from these paralytic illnesses remain unclear, although it would appear that time to recovery has been prolonged in many cases, and the degree of recovery remains uncertain.

TREATMENT IS SUPPORTIVE

The treatment of EV-D68 infection is mainly supportive, as no specific antiviral therapy is currently available for any of the enteroviruses. Critically ill patients require organ-specific supportive care.

Potential targets for novel antienteroviral therapies exist; some of the experimental compounds were initially evaluated for their activity against polioviruses or rhinoviruses.30

TESTING MAY HAVE A ROLE

In general, testing does not play a role in the management of patients with mild disease, but it may be indicated for epidemiologic purposes or for specific diagnosis in critically ill patients. Molecular techniques are commonly used to detect respiratory viruses from clinical samples, either as discrete tests or as a multiplex viral panel.

Since patients with EV-D68 infection typically have respiratory symptoms, the virus is generally tested for in nasal wash samples. However, depending on the clinical presentation, it may be appropriate to attempt to detect the virus from other sites using either PCR or culture.

Many clinical laboratories use real-time PCR assays designed to detect both rhinoviruses and enteroviruses, but these tests do not distinguish between the species. While more specific real-time PCR assays are available that generally distinguish rhinoviruses from enteroviruses,31 during the recent outbreak our laboratory observed that confirmed EV-D68 samples cross-reacted with rhinovirus. Most clinical laboratories do not routinely perform viral sequence analysis to specifically identify EV-D68, but this test may be obtained through state health departments and the CDC on a case-by-case basis.

Recently, the CDC’s enterovirus laboratory announced the development of a real-time PCR assay specifically for EV-D68, which may make specific detection more readily available.

INFECTION PREVENTION

The routes by which EV-D68 is transmitted are not fully understood. In contrast to most enteroviruses, which are spread in a fecal-oral manner, it is possible that EV-D68 is also spread through close respiratory or mucous contact.

For this reason, interim infection prevention guidelines issued by the CDC recommend that hospitals use droplet precautions along with contact or standard precautions, depending on the scenario.32 In our children’s hospital, we use droplet and contact precautions for hospitalized patients.

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