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Study: Enterovirus 71 had severe neurologic consequences
Pediatric enterovirus 71 “may be considered the new polio,” said researchers in a new study of 61 hospitalized children, which found EV71 to be...
MADRID – Ninety-two percent of Spanish children sickened during the first-ever outbreak of enterovirus-associated brain stem encephalitis in western Europe survived with no long-term sequelae, Nuria Worner, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
“We think that aggressive treatments should be restricted to those patients with important neurologic involvement,” declared Dr. Worner of Vall d’Hebron University Hospital in Barcelona. “We can say that no patients with milder involvement and without warning signs during the first 24 hours after onset of neurologic involvement went on to develop fulminant symptoms.”
Notable outbreaks of enterovirus A71 (EV-A71)-associated brain stem encephalitis occurred in Southeast Asia, Australia, and China in the late 1990s.
Dr. Worner reported on 196 children treated for laboratory-confirmed EV-A71–associated brain stem encephalitis at 16 Spanish hospitals in April-December 2016. Their median age was 25 months, 57% were male, and a median of 2 days of symptoms of mild viral illness transpired before neurologic symptoms arose. Prior to presenting to a hospital, 21% of the children had been diagnosed with hand-foot-and-mouth disease, and 13% with herpangina.
Initial preadmission symptoms included fever in 94% of cases, sleepiness in 86%, ataxia in 75%, tremor in 47%, myoclonus in 40%, and a rash in 26%.
Fifty-five percent of the children had EV RNA isolated from both throat and feces, 26% from the throat only, and 19% only from their feces. Eighty-seven percent of serotyped EV were EV-A71.
Ninety percent of children underwent lumbar puncture. Particularly noteworthy was the finding that EV was detected in the cerebrospinal fluid of a mere 3% of patients, although pleocytosis was present in 84%.
Brain MRI showed brain stem encephalitis along with myelitis in 50% of patients, brain stem myelitis without encephalitis in 29%, myelitis elsewhere in 2%, and normal findings in 19%.
Ground zero for the outbreak was Barcelona and the surrounding region of Catalonia; indeed, 130 of the 196 (66%) affected children came from there. The Catalan health department and pediatric infectious disease specialists quickly created standardized case severity definitions and treatment recommendations; they distributed them nationally.
Mild EV-A71–associated brain stem disease was defined as two or more of the following: tremor, myoclonus, mild ataxia, and/or significant drowsiness. The recommendation in these mild cases was for no treatment other than supportive care and careful in-hospital monitoring.
Patients with moderate involvement had to meet the definition for mild disease plus more pronounced ataxia or bulbar motor neuron involvement marked by slurred speech, drooling, dysphagia, apnea, abolition of the gag reflex, and/or an abnormal respiratory pattern. Moderately affected patients received two doses of intravenous immunoglobulin (IVIG), each dosed at 1 g/kg per 24 hours. Admission to the pediatric ICU was individualized for patients with moderate EV-A71–associated brain stem encephalitis.
Severe disease was categorized as bulbar motor neuron involvement plus neurogenic cardiorespiratory failure. Those patients were uniformly admitted to a pediatric ICU and given the two doses of IVIG. The need for systemic steroids was determined on an individual basis.
Forty percent of patients received IVIG and systemic steroids, 24% received IVIG only, 2% systemic steroids only, and 34% received no treatment other than supportive care.
Twenty-six percent of children were admitted to a pediatric ICU for a median stay of 3.5 days. Nine percent of children were placed on mechanical ventilation.
As the disease evolved, the most frequent neurologic complications included slurred speech in 15% of children, abnormal breathing pattern in 11%, seizures in 10%, acute flaccid paralysis in 9%, and cardiorespiratory failure with pulmonary edema in 9%, all occurring within the first hours after hospital admission.
The median hospital length of stay for the full study population was 6 days. The survival rate was 99.5%, with the sole death being due to cardiorespiratory failure.
With 1-6 months of follow-up since the acute episode of EV-A71–associated brain stem encephalitis, the long-term sequelae included two cases of limb paresis and two cases of paresis of a cranial nerve, one child with residual seizures, and one with hypoxic-ischemic encephalopathy.
Asked why the fatality rate in the Spanish outbreak was so much lower than in the earlier Australasian outbreaks, Dr. Worner cited Catalan physicians’ quick recognition of what was underway – and, more importantly, a difference in the EV-A71 viral subgenotype. Most of the most severe cases in Asia and Australia involved the C-4 subgenotype, while in Spain, the predominant subgenotype involved in the outbreak was C-1.
As for the curious finding that EV was detectable in the cerebrospinal fluid of a mere 3% of the Spanish children, she said the explanation is unknown. The two main possibilities are that the CNS symptoms were due to a parenchymal brain infection rather than to EV-A71 infection of meningeal tissue. Alternatively, the CNS involvement may have been a manifestation of an immunologic response to the infection, rather than being due to the virus itself.
Dr. Worner reported having no financial conflicts of interest.