Cluster of Acute Flaccid Myelitis Linked to Enterovirus D68

Pauline Anderson

January 30, 2015

Researchers at Children's Hospital Colorado have described what they believe is the country's first defined cluster of children presenting with acute flaccid paralysis or cranial nerve dysfunction that they are linking to an outbreak of enterovirus D68 (EV-D68).

In recent months, cases of respiratory-related infections from EV-D68 have been documented in various regions of the United States. Although findings from the Colorado cases don't prove that this enterovirus caused the neurologic deficits, researchers believe that several epidemiologic, virologic, and clinical factors point to an association.

EV-D68 could be emerging alongside other viruses that have been tied to outbreaks of acute flaccid paralysis in areas where polioviruses no longer circulate, said lead author Kevin Messacar, MD, assistant professor, pediatrics, and a pediatric infectious diseases physician and researcher, Children's Hospital Colorado, Aurora.

Dr Kevin Messacar

The authors describe the cluster in a paper published January 28 in The Lancet.

First isolated in 1962, human EV-D68 is 1 of more than 100 nonpolio enteroviruses. Biologically close to rhinoviruses, it belongs to the enterovirus D species within the Enterovirus genus. Although it has evolved to target the upper respiratory tract, it has the potential to also affect the nervous system.

Between August 1 and September 30, 2014, researchers documented a 36% increase in respiratory visits to the emergency department of Children's Hospital Colorado and a 77% increase in admissions for respiratory symptoms, compared with corresponding periods in 2012 and 2013.

During that same 2014 period, the number of nasopharyngeal samples testing positive for rhinovirus or enterovirus increased substantially. Of 25 specimens from children admitted to the intensive care unit with severe respiratory illness who tested positive for rhinovirus or enterovirus in the nasopharynx, researchers identified EV-D68 in 76%.

Researchers decided to probe this unusual situation further and developed a "case definition."

Case Definition

"Our case definition was any child who came into Children's Hospital Colorado during the period August 1 to October 31, 2014, with acute flaccid paralysis — weakness of limbs — with correlating spinal cord lesions in the grey matter, so we needed both clinical and imaging features," said Dr Messacar. "Or the children could have acute cranial nerve dysfunction — weakness of eyes, face muscles, bulbar muscles — that correlated with imaging changes in the brain stem."

The cluster of cases meeting this definition and described in the journal article included 12 children; 75% were male, and the median age was 11.5 years. Many of these children were already enrolled in an ongoing study looking at causes of central nervous system infections in children, said Dr Messacar.

Eight of the children (67%) were previously healthy, 3 had a history of asthma, and 1 had received a heart transplant. All but 1 child were fully vaccinated, including polio vaccines; 1 child was completely unvaccinated. No child had travelled outside the United States in the preceding 6 months.

Common Features

The cases had many common features. "All the children presented following a febrile upper respiratory illness and about a week later developed either weakness of muscles of the face, neck, arms or legs," said Dr Messacar. "The acute onset of weakness or flaccid paralysis is particularly unusual."

The researchers obtained nasopharynx specimens from 11 children. The specimens of 5 children tested positive for EV-D68. One of 8 throat samples tested positive for EV-D68 (in a child who was also positive for this virus in the nasopharynx). Tests from all children for whom rectal or stool specimens were obtained were negative for enteroviruses, including polioviruses.

Extensive Testing

Although the researchers carried out "fairly extensive testing," they didn't find EV-D68 — or any other viruses — in cerebrospinal fluid (CSF) samples. Dr Messacar stressed that it can be challenging to detect enteroviruses in the CSF.

"There are hypotheses that the virus is either gone from the spinal fluid by the time of a lumbar puncture, or the virus could be in the neural tissue and not in the spinal fluid itself," he said.

The fact that the virus wasn't detected in CSF "does not necessarily rule out the potential role of enterovirus D68," authors of an accompanying commentary agreed. Like the study authors, the commentators — Audrey Mirand and Hélène Peigue-Lafeuille, Virology Laboratory, National Reference Center for Enteroviruses and Parechoviruses, Clermont-Ferrand, France — noted that certain enteroviruses are more frequently recovered in peripheral samples, such as stool specimens or throat swabs.

"Clinical specimens including cerebrospinal fluid, respiratory tract specimens, serum samples, and two stool specimens should thus be collected early after disease onset and testing for infectious causes, including enteroviruses, should be rapidly undertaken."

Treatment Ineffective

The 12 children in the cluster received various therapeutic interventions, according to Dr Messacar. Nine (75%) received intravenous immunoglobulin (1 g/kg per day for 2 days). Four of these children and 1 additional child received intravenous methylprednisolone (30 mg/kg per day to a maximum of 1 g) for 3 to 5 days. Before intravenous immunoglobulin, 2 (17%) children underwent plasmapheresis for 3 days. Two (17%) children received an experimental antiviral drug (pocapavir).

"There was no evident short-term improvement after treatment with any of these therapies," said Dr Messacar.  "Physical and rehabilitation therapies are being provided to these children."

Of the 10 children with cranial nerve dysfunction, 3 (30%) have improved since the onset of their symptoms. As of December 1, 2014, all 10 children with limb weakness had residual deficits. It's unknown whether their paralysis will be permanent.

CDC Tracking

The Centers for Disease Control and Prevention (CDC) is tracking similar cases of neurologic illness. (The CDC uses a somewhat different case definition; according to Dr. Messacar, it focuses on flaccid paralysis with spinal cord lesions — and leaves out cranial nerve dysfunction with correlating brain stem lesions.)

As of January 14, 2015, the CDC had verified reports of 107 children in 34 US states who developed the same neurologic illness that is now being called acute flaccid myelitis (AFM).

Not all EV-D68 has a neurologic involvement or even severe illness. Millions of Americans likely have mild EV-D68 infections that go untreated or untested.

Earlier this month, Medscape Medical News reported that as of January 8, 2015, the CDC and state public health laboratories had confirmed 1153 cases of EV-D68, almost all of them involving children, and 13 deaths, dating from the middle of August 2014.

Targeting Children

Why does this enterovirus seem to target children? Little is known about immunity surrounding this pathogen, commented Dr Messacar. "We know that with many common viral diseases, children are predominantly affected as they are immunologically susceptible.  Once exposed, they gain immunity to the virus, preventing future infection later in life."

Although EV-D68 seems the logical culprit in this new spate of neurologic illnesses, especially because most children present with a fever, the connection between the neurologic symptoms and EV-D68 hasn't been firmly established.

"Detection of enterovirus D68 in respiratory samples against a backdrop of nationwide outbreaks might be coincidental on the basis that this virus was not isolated in all children," write the commentators. However, they pointed out that delayed collection of nasopharyngeal aspirates after respiratory illness (median, 10 days) from 11 children in the study "might have reduced the opportunity to isolate it."

Déjà Vu

The characteristics of the new cases — the limb weakness, nerve dysfunction, abnormalities of the spinal cord grey matter, and occurrence mainly children — are similar to what was seen in the context of polio many years ago. Indeed, the commentary authors said the new data "evoke a feeling of déjà vu." They noted the "striking similarities" with infections from not only polioviruses but also enterovirus A71, which was linked to outbreaks of hand, foot, and mouth disease in Taiwan in 1998.

But while some experts wonder whether this emerging enterovirus will fill a vacuum left by the eradication of polio, Dr Messacar isn't so sure.

"There is no scientific evidence for 'replacement disease' or a 'vacuum effect' for viral diseases," he told Medscape Medical News. "While this cluster of cases is potentially associated with EV-D68 and is newly recognized, there is no suggestion that this would be triggered by, or relating in any way to, the eradication efforts with poliovirus."

Researchers need to make some scientific headway before a vaccine against AFM can be developed, according to Dr Messacar.

"The etiologic link between AFM and EV-D68 needs to be investigated further through case-control studies of stored nasopharyngeal samples and serologic testing. And surveillance needs to be established to determine if and when EV-D68 is to recirculate."

These viruses tend to appear in late fall and all but disappear over the winter, he said.

"If further investigation confirms the association between enterovirus D68 and neurologic disease, and enterovirus D68 infections continue to happen in an endemic or epidemic pattern, development of effective antiviral or immunomodulatory therapies and vaccines will emerge as scientific priorities."

The editorial writers also stressed the need for continued surveillance. "Surveillance of acute flaccid paralysis is a key and sensitive instrument for detection of poliomyelitis cases and the emergence of other potential neurotropic enteroviruses or other pathogens," they conclude.

Dr Messacar and the commentators have disclosed no relevant financial relationships.

Lancet. Published online January 29, 2015. Abstract Editorial

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