The review article examines how the rapid evolution of enteroviruses complicates disease diagnosis, treatment, and prevention in children

Enteroviruses (EVs) are a diverse group of viruses and a common cause of multiple infections in children. A recent Pediatric Investigation review examines EV infections, highlighting the challenges posed by viral diversity, rapid evolution, immune evasion, and limited treatment and vaccine options. Currently, no specific antiviral treatment exists for EV, and prevention is limited since current vaccines cover only certain serotypes, underscoring the need for further research to expand both preventive and therapeutic options.

Enterovirus (EV) infections in children can result in severe diseases ranging from hand-foot-and-mouth disease and herpangina to meningitis, hepatitis, pneumonia, and acute flaccid paralysis. Patients and asymptomatic carriers are the main sources of transmission. EVs are mainly transmitted through the fecal–oral route and respiratory droplets. Children under 5 years of age may be at high risk of symptomatic and severe EV infections due to their immature immune systems. Although most infections are mild or self-limiting, certain EV infections can cause severe complications.

A recent review article made available online on 21 August 2026 in the journal Pediatric Investigation highlights rapid viral evolution combined with shifting dominant strains and antigenic variation as a major obstacle to EV prevention and control. The RNA-dependent RNA polymerase lacks proofreading capability, resulting in a high mutation rate. In addition to point mutations, different EV types or strains can undergo recombination when they co-infect host cells, generating additional genetic diversity. Professor Xiangpeng Chen notes, “A better understanding of EV pathogenesis, host–virus interactions, and clinical manifestations is essential for improving precision diagnosis and developing effective antiviral therapies and vaccines.”

Building on the finding that “recombination serves as the core driver of EV evolution,” the authors note that recombination can generate genetic diversity more efficiently than point mutations. For instance, the C4 genotype of EV-A71 became the predominant circulating strain in China in 2004 and has generated multiple complex evolutionary branches through continuous interserotype recombination. Prof. Chen says, “This ‘modular’ genetic exchange produces genetic diversity more efficiently than point mutations, enabling EV to rapidly adapt to changes in the host environment.”

The review then examines the mechanisms through which EVs invade host cells and establish infection. The viral replication cycle proceeds through six stages: attachment, entry, uncoating, genome replication and translation, viral assembly, and release. Different EV species use distinct cellular receptors, which influence their host range, tissue tropism, and pathogenic mechanisms. Following receptor binding and cell entry, conformational changes in the viral capsid facilitate the release of the viral RNA genome into the cytoplasm.

Once inside the cell, EVs remodel host intracellular membranes to create replication organelles, primarily derived from the endoplasmic reticulum and Golgi membranes. These structures provide a protected platform for viral RNA synthesis. Prof. Chen explains, “These membranous structures not only concentrate viral replication factors and RNA templates but also protect viral replication intermediates from host innate immune recognition.”

EVs can simultaneously trigger and suppress host immune responses. Viral RNA activates innate antiviral pathways, while viral proteins interfere with immune signaling to promote viral survival and dissemination. Clinically, most hand, foot, and mouth disease (HFMD) cases are mild, but EV-A71 can cause severe neurological and cardiopulmonary complications. Other EVs are associated with meningitis, encephalitis, acute flaccid paralysis, myocarditis, hepatitis, respiratory infections, and acute hemorrhagic conjunctivitis, while EV-D68 is particularly associated with acute flaccid myelitis.

Real-time RT-PCR is the mainstay of EV diagnosis because of its speed and sensitivity, although false-negative results can occur because of low viral loads, delayed sampling, inappropriate specimens, or primer mismatches. Treatment remains primarily supportive, as no approved specific antiviral therapy is available. Several antiviral approaches, including capsid binders, protease and polymerase inhibitors, monoclonal antibodies, and host-targeting drugs, remain under investigation. The authors further explain, “Although RT-PCR provides rapid and sensitive detection of EV, negative results do not completely rule out infection, particularly when viral load is low or specimens are collected late.”

Prevention therefore remains essential. Inactivated EV-A71 vaccines used in China provide strong protection against severe EV-A71 disease but do not protect against other major HFMD-associated serotypes, including CVA16, CVA6, and CVA10. The review therefore emphasizes the need for multivalent and broad-spectrum vaccines, alongside hand hygiene, environmental disinfection, safe food and water practices, early diagnosis, isolation, and strengthened surveillance. The authors say, “Given the diversity of EV types, the development of multivalent vaccines represents an important future direction for enterovirus prevention.”

Overall, the authors highlight that effective EV control will require an integrated approach combining improved surveillance, rapid diagnosis, supportive clinical care, broad-spectrum antiviral development, and wider vaccine protection.