Despite advances in the diagnosis and understanding of enterovirus pathogenesis, specific antiviral treatments and vaccine protection may be limited for enterovirus infections among children.
Investigators reviewed current evidence on the epidemiology; virology; viral entry mechanisms; virus-host interactions; clinical diagnosis; and management, prevention, and control of EV infections. They synthesized recent advances and barriers to diagnosis, treatment, antiviral development, and vaccination across the spectrum of pediatric enterovirus (EV) infections–including neonatal sepsis, hand-foot-and-mouth disease (HFMD), myocarditis, pneumonia, meningitis, encephalitis, and acute flaccid myelitis, and mortality in severe cases.
The investigators emphasized that the virus' diversity, rapid evolution, and antigenic variation complicate prevention and control.
Molecular testing has become central to EV diagnosis. Reverse transcription–polymerase chain reaction targeting conserved genomic regions has a sensitivity of more than 95% and turnaround time of less than 6 hours. Broad-spectrum primers can offer a wide range of EV detection, whereas VP1-specific primers can facilitate serotyping. However, genetic diversity can result in primer mismatches and false negatives. The investigators advised interpreting molecular results alongside clinical manifestations and epidemiologic information.
EVs account for about 58% of meningitis or encephalitis cases in children, about 5% to 10% of whom may develop clinical features of encephalitis, including altered consciousness or seizures. Although most pediatric patients with EV-related central nervous system disease recover within 3 to 7 days of symptom onset, severe disease and death can occur, particularly among immunocompromised patients.
Treatment remains primarily supportive and symptomatic because no antiviral drug has been approved for routine clinical use against EV infections. Management varies by clinical phenotype and may include fluid and electrolyte management, antipyresis, analgesia, respiratory support, seizure control, intracranial pressure management, and circulatory support. Investigational approaches include agents targeting viral entry, uncoating, protease activity, and RNA replication, as well as host-directed therapies and immunotherapies, but most remain experimental or tested in limited clinical settings.
Clinical development of several antiviral candidates has also stalled. Pleconaril and vapendavir have reached phase 2 testing, whereas pocapavir completed phase 2 human poliovirus challenge studies but did not advance to routine clinical use because of limited efficacy and emergence of resistance. Rupintrivir also completed phase 2 trials but was discontinued after failing to demonstrate efficacy in natural infection studies. Other candidates remain predominantly preclinical.
Intravenous immunoglobulin has been used in neonates and patients with severe disease, with improved outcomes reported in some cases, but large randomized controlled trials are lacking. Evidence for interferon treatment also remains inconsistent despite a randomized double-blind study suggesting faster HFMD symptom resolution with topical recombinant human interferon alpha-2b.
Vaccination illustrated the progress and limitations of current prevention. The inactivated EV-A71 vaccine has shown an efficacy of more than 90% against severe HFMD, brainstem encephalitis, and cardiopulmonary failure in phase 3 trials in China. Protective neutralizing antibodies were maintained for a median of 5 to 6 years following 2 doses. However, efficacy against milder symptoms was approximately 70% to 80%, and vaccines for other human EV infections remain unavailable.
EV-A71 vaccines do not provide cross-protection against other EVs associated with HFMD, including coxsackievirus A16, A6, and A10. The investigators identified multivalent and broad-spectrum vaccines as future priorities but noted challenges including antigen compatibility, immune interference, manufacturing and quality-control complexity, high serotype specificity, viral mutation, and a lack of standardized evaluation systems for broad-spectrum targets.
Because of the genetic diversity of EVs, activity against 1 virus may not extend to another. Rapid mutation can select resistant variants, while severe EV disease is relatively uncommon, unpredictable, and clinically heterogeneous. Treatments for central nervous system, myocardial, hepatic, and neonatal disease also face additional requirements for tissue penetration and pediatric safety.
“Future research should prioritize broad-spectrum agents with high resistance barriers, and acceptable pediatric safety,” wrote lead study author Xiangpeng Chen, of Beijing Children’s Hospital at the Capital Medical University of the National Center for Children’s Health, and colleagues.
The study authors declared no conflicts of interest.
Source: Pediatric Investigation