Human parechovirus infection in neonates and young infants: Clinical features, diagnostic challenges, and neurodevelopmental outcomes.

Human parechoviruses (HPeVs) are increasingly recognized as viral pathogens in neonates and young infants. Among the 18 identified genotypes, HPeV-3 is most strongly associated with severe disease during early infancy, including sepsis-like illness and central nervous system (CNS) infection. Clinical recognition can be challenging because typical laboratory features of CNS infection are frequently absent: cerebrospinal fluid (CSF) pleocytosis is often lacking, and inflammatory markers are usually normal or only mildly elevated. Severe cases may present with marked hyperferritinemia and systemic inflammatory activation resembling hemophagocytic lymphohistiocytosis. This narrative review summarizes current evidence on the epidemiology, transmission, pathophysiology, clinical manifestations, diagnostic approaches, management, and long-term outcomes of HPeV infection in neonates and young infants, with particular focus on HPeV-3. Evidence from recent cohort studies and outbreak investigations highlights the strong age dependence of severe disease, which predominantly affects infants younger than three months. Neuroimaging frequently reveals characteristic white matter injury, and the presence of seizures or extensive diffusion restriction on MRI is associated with increased risk of adverse neurodevelopmental outcomes. Diagnosis relies primarily on molecular detection using reverse-transcription polymerase chain reaction, with blood testing often providing higher diagnostic yield than CSF alone. Although no specific antiviral therapy is currently available, establishing a virological diagnosis has important clinical implications, including antimicrobial stewardship and identification of infants requiring neurodevelopmental follow-up. Despite increasing recognition of HPeV-3 infection, important knowledge gaps remain regarding mechanisms of brain injury, optimal diagnostic strategies, and long-term outcomes. Further prospective studies are needed to guide clinical management and inform preventive strategies.