Is EV-D68 infection a cause of acute flaccid myelitis in children?
H. CodyMeissner, M.D., FAAP
Enterovirus D68 (EV-D68) was first identified in California in 1962. Initially, it
was classified as a rhinovirus but now is classified as one of more than 100 non-polio
enteroviruses. For several decades after the initial description, EV-D68 was rarely
recovered from patients. Between 2008 and 2014, the virus was isolated occasionally
from clusters of children younger than 5 years of age with severe respiratory illness.
Which of the following statements are false?
a) Most enterovirus infections are asymptomatic.
b) Infants and children are at increased risk for infection by EV-D68 relative to
adults because they are less likely to have developed immunity from a previous infection.
c) Enterovirus infections are most common in the summer and fall in the U.S.
d) EV-D68 is reliably inactivated with alcohol-based hand rub.
e) EV-D68 is a documented cause of acute flaccid myelitis (AFM).
Answer: d and e are not correct
In the summer and fall of 2014, a nationwide outbreak of EV-D68 occurred and was associated
with severe respiratory tract disease. In September 2014, the Centers for Disease
Control and Prevention (CDC) began to receive reports of AFM, and a possible association
with EV-D68 was considered. During this enterovirus season, the CDC confirmed more
than 1,100 infections, largely among children, many of whom had a history of asthma.
Many more people likely experienced a mild EV-D68 infection for which medical treatment
was not sought or from whom cultures were not obtained.
During the 2015 enterovirus season, the CDC received about 700 specimens for enterovirus
testing, and none were positive for EV-D68. During most of 2016, sporadic EV-D68 detections
occurred in the U.S., but evidence of unusual activity was not apparent. (See AAP News article “CDC: 108 cases of acute flaccid myelitis this year,” http://bit.ly/2hYZ9k7.)
EV-D68 should be considered especially during the summer and fall as a cause of unexplained,
severe acute respiratory illness in children especially during clusters of disease.
Nasopharyngeal or oropharyngeal specimens that test positive for enterovirus or rhinovirus
should be considered for molecular testing using real-time polymerase chain reaction
(PCR) or nested PCR. Virus may be detected in stool or rectal swabs for a longer period
than from respiratory specimens.
Infection-control precautions for suspected cases should include standard, contact
and droplet precautions. Non-enveloped viruses such as EV-D68 may be less susceptible
to alcohol inactivation than enveloped viruses. Hand hygiene with soap and water upon
removal and prior to donning of gloves may be preferred to alcohol-based hand rub.
Between 2012 and 2015, an increasing number of reports of a distinct syndrome of acute
flaccid paralysis with anterior myelitis was noted. Symptoms were similar to those
caused by polio viruses and to avoid confusion, the term acute flaccid myelitis (AFM)
was proposed. AFM is defined as a case of acute flaccid weakness with either spinal
cord gray matter lesions detected on imaging or evidence of spinal cord motor neuron
injury on electrodiagnostic testing.
A typical case of AFM is preceded by a median of five days with rhinorrhea, cough
or pharyngitis. Gastrointestinal symptoms (vomiting, diarrhea) are reported in about
two-thirds of patients. Most patients report improvement of symptoms prior to return
of fever and onset of muscle stiffness or pain around the time of neurologic deficit
onset. Over a period of a few hours to a few days, there is progression from full
strength to neurologic deficit. Weakness is flaccid with decreased or absent reflexes
in one to four extremities and generally is asymmetric. Limb weakness may be accompanied
by cranial nerve dysfunction resulting in hypophonia (soft speech), dysarthria, dysphagia,
facial weakness and diplopia.
Optimal management of a patient with AFM is not clear. Immunomodulatory agents, antiviral
agents, intravenous immune globulin, high-dose corticosteroids and plasmapheresis
have not been evaluated in a controlled fashion, and no significant improvement or
deterioration has been described with these interventions.
Three antiviral drugs in clinical trials for treatment of other enterovirus infections
(pleconaril, pocapavir, vapendavir) do not demonstrate activity against EV-D68 in
vitro. Fluoxetine (Prozac), a selective serotonin reuptake inhibitor, interferes with
EV-D68 replication in vitro, but its role as a therapeutic agent has not been evaluated.
Causes of AFM include polio virus and non-polio enteroviruses (such as enteroviruses
A71 and D70), West Nile virus, Japanese encephalitis virus, St. Louis encephalitis
virus and adenoviruses. Non-infectious causes include environmental toxins, genetic
disorders, Guillain-Barré syndrome and acute disseminated encephalomyelitis.
Although a mild to moderate pleocytosis in the cerebrospinal fluid (CSF) generally
is present, no infectious agent has been isolated consistently from the CSF of patients
with AFM. Despite similarities with poliomyelitis, the inability to detect wild type
polio virus or polio vaccine-derived stains from the stool of patients with AFM indicates
that poliovirus is unlikely to be involved.
The proposed association between EV-D68 infection and AFM is based on epidemiologic
evidence. The increase in AFM and EV-D68 infections both temporally and geographically
suggests an association. The biologic plausibility of an association is substantiated
by evidence supporting other non-polio enteroviruses as a cause of paralysis.
Dr. Meissner is professor of pediatrics at Floating Hospital for Children, Tufts Medical
Center. He also is an ex officio member of the AAP Committee on Infectious Diseases
and associate editor of the AAP Visual Red Book.